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  • 1. Abel, Olubunmi
    et al.
    Powell, John F.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    ALSoD: A user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics2012In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 33, no 9, p. 1345-1351Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is the commonest adult onset motor neuron disease, with a peak age of onset in the seventh decade. With advances in genetic technology, there is an enormous increase in the volume of genetic data produced, and a corresponding need for storage, analysis, and interpretation, particularly as our understanding of the relationships between genotype and phenotype mature. Here, we present a system to enable this in the form of the ALS Online Database (ALSoD at http://alsod.iop.kcl.ac.uk), a freely available database that has been transformed from a single gene storage facility recording mutations in the SOD1 gene to a multigene ALS bioinformatics repository and analytical instrument combining genotype, phenotype, and geographical information with associated analysis tools. These include a comparison tool to evaluate genes side by side or jointly with user configurable features, a pathogenicity prediction tool using a combination of computational approaches to distinguish variants with nonfunctional characteristics from disease-associated mutations with more dangerous consequences, and a credibility tool to enable ALS researchers to objectively assess the evidence for gene causation in ALS. Furthermore, integration of external tools, systems for feedback, annotation by users, and two-way links to collaborators hosting complementary databases further enhance the functionality of ALSoD. Hum Mutat 33:1345-1351, 2012. (c) 2012 Wiley Periodicals, Inc.

  • 2. Abel, Olubunmi
    et al.
    Powell, John F
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    Credibility analysis of putative disease-causing genes using bioinformatics2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e64899-Article in journal (Refereed)
    Abstract [en]

    Background: Genetic studies are challenging in many complex diseases, particularly those with limited diagnostic certainty, low prevalence or of old age. The result is that genes may be reported as disease-causing with varying levels of evidence, and in some cases, the data may be so limited as to be indistinguishable from chance findings. When there are large numbers of such genes, an objective method for ranking the evidence is useful. Using the neurodegenerative and complex disease amyotrophic lateral sclerosis (ALS) as a model, and the disease-specific database ALSoD, the objective is to develop a method using publicly available data to generate a credibility score for putative disease-causing genes.

    Methods: Genes with at least one publication suggesting involvement in adult onset familial ALS were collated following an exhaustive literature search. SQL was used to generate a score by extracting information from the publications and combined with a pathogenicity analysis using bioinformatics tools. The resulting score allowed us to rank genes in order of credibility. To validate the method, we compared the objective ranking with a rank generated by ALS genetics experts. Spearman's Rho was used to compare rankings generated by the different methods.

    Results: The automated method ranked ALS genes in the following order: SOD1, TARDBP, FUS, ANG, SPG11, NEFH, OPTN, ALS2, SETX, FIG4, VAPB, DCTN1, TAF15, VCP, DAO. This compared very well to the ranking of ALS genetics experts, with Spearman's Rho of 0.69 (P = 0.009).

    Conclusion: We have presented an automated method for scoring the level of evidence for a gene being disease-causing. In developing the method we have used the model disease ALS, but it could equally be applied to any disease in which there is genotypic uncertainty.

  • 3.
    Ahmadi, Mahboobah
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Liu, Jing-Xia
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Stål, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
    Pedrosa-Domellöf, Fatima
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Ophthalmology.
    Human extraocular muscles in ALS2010In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 51, no 7, p. 3494-3501Article in journal (Refereed)
    Abstract [en]

    PURPOSE. To investigate the general morphology, fiber type content, and myosin heavy chain (MyHC) composition of extraocular muscles (EOMs) from postmortem donors with amyotrophic lateral sclerosis (ALS) and to evaluate whether EOMs are affected or truly spared in this disease. METHODS. EOM and limb muscle samples obtained at autopsy from ALS donors and EOM samples from four control donors were processed for immunohistochemistry with monoclonal antibodies against distinct MyHC isoforms and analyzed by SDS-PAGE. In addition, hematoxylin and eosin staining and nicotinamide tetrazolium reductase (NADH-TR) activity were studied. RESULTS. Wide heterogeneity was observed in the appearance of the different EOMs from each single donor and between donors, irrespective of ALS type or onset. Pathologic morphologic findings in ALS EOMs included presence of atrophic and hypertrophic fibers, either clustered in groups or scattered; increased amounts of connective tissue; and areas of fatty replacement. The population of fibers stained with anti-MyHCslow tonic was smaller than that of MyHCIpositive fibers and was mostly located in the orbital layer in most of the ALS EOM samples, whereas an identical staining pattern for both fiber populations was observed in the control specimens. MyHCembryonic was notably absent from the ALS EOMs. CONCLUSIONS. The EOMs showed signs of involvement with altered fiber type composition, contractile protein content, and cellular architecture. However, when compared to the limb muscles, the EOMs were remarkably preserved. EOMs are a useful model for the study of the pathophysiology of ALS.

  • 4.
    Akimoto, Chizuru
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Backlund, Irene
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Andersson, Jörgen
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    No GGGGCC-hexanucleotide repeat expansion in C9ORF72 in parkinsonism patients in Sweden2013In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, Vol. 14, no 1, p. 26-29Article in journal (Refereed)
    Abstract [en]

    An intronic GGGGCC-hexanucleotide repeat expansion in C9ORF72 was recently identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. Some amyotrophic lateral sclerosis patients have signs of parkinsonism, and many parkinsonism patients develop dementia. In this study we examined if the hexanucleotide repeat expansion was present in parkinsonism patients, to clarify if there could be a relationship between the repeat expansion and disease. We studied the size of the hexanucleotide repeat expansion in a well defined population-based cohort of 135 Parkinson's disease patients and 39 patients with atypical parkinsonism and compared with 645 Swedish control subjects. We found no correlation between Parkinson's disease or atypical parkinsonism and the size of the GGGGCC repeat expansion in C9ORF72. In conclusion, this GGGGCC-repeat expansion in C9ORF72 is not a cause of parkinsonism in the Swedish population.

  • 5.
    Akimoto, Chizuru
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Volk, Alexander E.
    van Blitterswijk, Marka
    Van den Broeck, Marleen
    Leblond, Claire S.
    Lumbroso, Serge
    Camu, William
    Neitzel, Birgit
    Onodera, Osamu
    van Rheenen, Wouter
    Pinto, Susana
    Weber, Markus
    Smith, Bradley
    Proven, Melanie
    Talbot, Kevin
    Keagle, Pamela
    Chesi, Alessandra
    Ratti, Antonia
    van der Zee, Julie
    Alstermark, Helena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Calini, Daniela
    Nordin, Angelica
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tradowsky, Daniela C.
    Just, Walter
    Daoud, Hussein
    Angerbauer, Sabrina
    DeJesus-Hernandez, Mariely
    Konno, Takuya
    Lloyd-Jani, Anjali
    de Carvalho, Mamede
    Mouzat, Kevin
    Landers, John E.
    Veldink, Jan H.
    Silani, Vincenzo
    Gitler, Aaron D.
    Shaw, Christopher E.
    Rouleau, Guy A.
    van den Berg, Leonard H.
    Van Broeckhoven, Christine
    Rademakers, Rosa
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Kubisch, Christian
    A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories2014In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 51, no 6, p. 419-424Article in journal (Refereed)
    Abstract [en]

    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.

  • 6.
    Andersen, Peter
    et al.
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Borasio, G D
    Dengler, R
    Hardiman, O
    Kollewe, K
    Leigh, P N
    Pradat, P-F
    Silani, V
    Tomik, B
    EFNS task force on management of amyotrophic lateral sclerosis: guidelines for diagnosing and clinical care of patients and relatives.2005In: European journal of neurology, ISSN 1351-5101, Vol. 12, no 12, p. 921-38Article in journal (Refereed)
  • 7.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    ALS and FTD: two sides of the same coin?2013In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 12, no 10, p. 937-938Article in journal (Other academic)
  • 8.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Mutation in C9orf72 changes the boundaries of ALS and FTD2012In: Lancet Neurology, ISSN 1474-4422, E-ISSN 1474-4465, Vol. 11, no 3, p. 205-207Article in journal (Refereed)
  • 9.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Abrahams, Sharon
    Borasio, Gian D.
    de Carvalho, Mamede
    Chio, Adriano
    Van Damme, Philip
    Hardiman, Orla
    Kollewe, Katja
    Morrison, Karen E.
    Petri, Susanne
    Pradat, Pierre-Francois
    Silani, Vincenzo
    Tomik, Barbara
    Wasner, Maria
    Weber, Markus
    EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS): revised report of an EFNS task force2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no 3, p. 360-E24Article in journal (Refereed)
    Abstract [en]

    Background: The evidence base for the diagnosis and management of amyotrophic lateral sclerosis (ALS) is weak. Objectives: To provide evidence-based or expert recommendations for the diagnosis and management of ALS based on a literature search and the consensus of an expert panel. Methods: All available medical reference systems were searched, and original papers, meta-analyses, review papers, book chapters and guidelines recommendations were reviewed. The final literature search was performed in February 2011. Recommendations were reached by consensus. Recommendations: Patients with symptoms suggestive of ALS should be assessed as soon as possible by an experienced neurologist. Early diagnosis should be pursued, and investigations, including neurophysiology, performed with a high priority. The patient should be informed of the diagnosis by a consultant with a good knowledge of the patient and the disease. Following diagnosis, the patient and relatives/carers should receive regular support from a multidisciplinary care team. Medication with riluzole should be initiated as early as possible. Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted. Percutaneous endoscopic gastrostomy feeding improves nutrition and quality of life, and gastrostomy tubes should be placed before respiratory insufficiency develops. Non-invasive positive-pressure ventilation also improves survival and quality of life. Maintaining the patient's ability to communicate is essential. During the entire course of the disease, every effort should be made to maintain patient autonomy. Advance directives for palliative end-of-life care should be discussed early with the patient and carers, respecting the patient's social and cultural background.

  • 10.
    Andersen, Peter M.
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Al-Chalabi, Ammar
    Clinical genetics of amyotrophic lateral sclerosis: what do we really know?2011In: Nature Reviews Neurology, ISSN 1759-4758, E-ISSN 1759-4766, Vol. 7, no 11, p. 603-615Article, review/survey (Refereed)
    Abstract [en]

    Hereditary amyotrophic lateral sclerosis (ALS) encompasses a group of genetic disorders characterized by adult-onset loss of the lower and upper motor neuron systems, often with involvement of other parts of the nervous system. Cases of hereditary ALS have been attributed to mutations in 12 different genes, the most common being SOD1, FUS and TARDBP-mutations in the other genes are rare. The identified genes explain 25-35% of cases of familial ALS, but identifying the remaining genes has proved difficult. Only a few genes seem to account for significant numbers of ALS cases, with many others causing a few cases each. Hereditary ALS can be inherited in an autosomal dominant, autosomal recessive or X-linked manner, and families with low disease penetrance are frequently observed. In such families, the genetic predisposition may remain unnoticed, so many patients carry a diagnosis of isolated or sporadic ALS. The only clinical feature that distinguishes recognized hereditary from apparently sporadic ALS is a lower mean age of onset in the former. All the clinical features reported in hereditary cases (including signs of extrapyramidal, cerebellar or cognitive involvement) have also been observed in sporadic cases. Genetic counseling and risk assessment in relatives depend on establishing the specific gene defect and the disease penetrance in the particular family.

  • 11.
    Andersén, Peter
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Bäckström, Torbjörn
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
    Dahlquist, Gisela
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Damber, Jan-Erik
    Engström-Laurent, Anna
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Gustafson, Yngve
    Umeå University, Faculty of Medicine, Department of Community Medicine and Rehabilitation, Geriatric Medicine.
    Hjemdahl, Paul
    Korsgren, Olle
    Olsson, Håkan
    Wiberg, Mikael
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Hand Surgery.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Svensk medicinsk forskning behöver inte mer styrning2014In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 111, no 22-23, p. 980-981Article in journal (Other (popular science, discussion, etc.))
  • 12.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Antti, Henrik
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Changes in the spinal cord proteome of an amyotrophic lateral sclerosis murine model determined by differential in-gel electrophoresis2009In: Molecular and cellular proteomics, ISSN 1535-9484, Vol. 8, no 6, p. 1306-1317Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by loss of motor neurons resulting in progressive paralysis. To date, more than 140 different mutations in the gene encoding CuZn-superoxide dismutase (SOD1) have been associated with ALS. Several transgenic murine models exist in which various mutant SOD1s are expressed. We have used differential in-gel electrophoresis (DIGE) to analyze the changes in the spinal cord proteome induced by expression of the unstable SOD1 truncation mutant G127insTGGG (G127X) in mice. Unlike mutants used in most other models, G127X lacks SOD activity and is present at low levels, thus reducing the risk of overexpression artifacts. The mice were analyzed at their peak body weights, just before onset of symptoms. Variable importance plot (VIP) analysis showed that 420 of 1,800 detected protein spots contributed significantly to the differences between the groups. By MALDI-TOF MS analysis, 54 proteins were identified. One spot was found to be a covalently linked mutant SOD1 dimer, apparently analogous to SOD1 immunoreactive bands migrating at double the molecular weight of SOD1 monomers previously detected in humans and mice carrying mutant SOD1s and in sporadic ALS cases. Analyses of affected functional pathways, and the subcellular representation of alterations suggest that the toxicity exerted by mutant SODs induces oxidative stress and affects mitochondria, cellular assembly/organization, and protein degradation.

  • 13.
    Bergemalm, Daniel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Forsberg, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Srivastava, Vaibhav
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wingsle, Gunnar
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice2010In: Journal of Neurochemistry, ISSN 0022-3042, E-ISSN 1471-4159, Vol. 114, no 2, p. 408-418Article in journal (Refereed)
    Abstract [en]

    Mutant superoxide dismutase-1 (SOD1) causes amyotrophic lateral sclerosis (ALS) through a cytotoxic mechanism of unknown nature. A hallmark in ALS patients and transgenic mouse models carrying human SOD1 (hSOD1) mutations are hSOD1-immunoreactive inclusions in spinal cord ventral horns. The hSOD1 inclusions may block essential cellular functions or cause toxicity through sequestering of other proteins. Inclusions from four different transgenic mouse models were examined after density gradient ultracentrifugation. The inclusions are complex structures with heterogeneous densities and are disrupted by detergents. The aggregated hSOD1 was mainly composed of subunits that lacked the native stabilizing intra-subunit disulfide bond. A proportion of subunits formed hSOD1 oligomers or was bound to other proteins through disulfide bonds. Dense inclusions could be isolated and the protein composition was analyzed using proteomic techniques. Mutant hSOD1 accounted for half of the protein. Ten other proteins were identified. Two were cytoplasmic chaperones, four were cytoskeletal proteins, and 4 were proteins that normally reside in the endoplasmic reticulum (ER). The presence of ER proteins in inclusions containing the primarily cytosolic hSOD1 further supports the notion that ER stress is involved in ALS.

  • 14.
    Bergh, Johan
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Graffmo, Karin Sixtensdotter
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Jonsson, P. Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Lang, Lisa
    Stockholm, Sweden.
    Danielsson, Jens
    Stockholm, Sweden.
    Oliveberg, Mikael
    Stockholm, Sweden.
    Marklund, Stefan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Structural and kinetic analysis of protein-aggregate strains in vivo using binary epitope mapping2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 14, p. 4489-4494Article in journal (Refereed)
    Abstract [en]

    Despite considerable progress in uncovering the molecular details of protein aggregation in vitro, the cause and mechanism of protein-aggregation disease remain poorly understood. One reason is that the amount of pathological aggregates in neural tissue is exceedingly low, precluding examination by conventional approaches. We present here a method for determination of the structure and quantity of aggregates in small tissue samples, circumventing the above problem. The method is based on binary epitope mapping using anti-peptide antibodies. We assessed the usefulness and versatility of the method in mice modeling the neurodegenerative disease amyotrophic lateral sclerosis, which accumulate intracellular aggregates of superoxide dismutase-1. Two strains of aggregates were identified with different structural architectures, molecular properties, and growth kinetics. Both were different from superoxide dismutase-1 aggregates generated in vitro under a variety of conditions. The strains, which seem kinetically under fragmentation control, are associated with different disease progressions, complying with and adding detail to the growing evidence that seeding, infectivity, and strain dependence are unifying principles of neurodegenerative disease.

  • 15.
    Bergström, Petra
    et al.
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    von Otter, Malin
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Nilsson, Staffan
    Institute of Mathematical Sciences, Department of Mathematical Statistics, Chalmers University of Technology, Gothenburg, Sweden.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Michael
    Institute of Neuroscience and Physiology, Centre for Brain Repair and Rehabilitation, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden and Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hammarsten, Ola
    Institute of Biomedicine, Department of Clinical Chemistry and Transfusion Medicine, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden.
    Zetterberg, Henrik
    Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden and UCL Institute of Neurology, London, UK.
    Association of NFE2L2 and KEAP1 haplotypes with amyotrophic lateral sclerosis2014In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, Vol. 15, no 1-2, p. 130-137Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron syndrome influenced by oxidative stress. The transcription factor Nrf2 and its repressor Keap1 constitute an important defence system in cellular protection against oxidative stress. Here we hypothesize that common genetic variations in the genes NFE2L2 and KEAP1, encoding Nrf2 and Keap1, may influence the risk and phenotype of ALS. Five hundred and twenty-two Swedish patients with sporadic ALS (SALS) and 564 Swedish control subjects were studied. Eight tag SNPs in NFE2L2 and three tag SNPs in KEAP1 were genotyped by allelic discrimination and three functional NFE2L2 promoter SNPs were genotyped by sequencing. One NFE2L2 haplotype (GGGAC) was associated with decreased risk of SALS (OR = 0.62 per allele, p = 0.003) and one haplotype in KEAP1 (CGG) was associated with later SALS onset (+3.4 years per allele, p = 0.015). When stratified by subgroup, one haplotype in NFE2L2, GAGCAGA including three functional promoter SNPs associated with high Nrf2 protein expression, was associated with 4.0 years later disease onset per allele in subgroup ALS (p = 0.008). In conclusion, these results suggest that variations in NFE2L2 and KEAP1, encoding two central proteins in cellular oxidative stress defence, may influence SALS pathogenesis.

  • 16.
    Birve, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Neuwirth, Christoph
    Weber, Markus
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Jonsson, Per Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    A novel SOD1 splice site mutation associated with familial ALS revealed by SOD activity analysis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 21, p. 4201-4206Article in journal (Refereed)
    Abstract [en]

    More than 145 mutations have been found in the gene CuZn-Superoxide dismutase (SOD1) in patients with amyotrophic lateral sclerosis (ALS). The vast majority are easily detected nucleotide mutations in the coding region. In a patient from a Swiss ALS family with half-normal erythrocyte SOD1 activity, exon flanking sequence analysis revealed a novel thymine to guanine mutation 7 bp upstream of exon 4 (c.240-7T>G). The results of splicing algorithm analyses were ambiguous, but five out of seven analysis tools suggested a potential novel splice site that would add six new base pairs to the mRNA. If translated, this mRNA would insert Ser and Ile between Glu78 and Arg79 in the SOD1 protein. In fibroblasts from the patient, the predicted mutant transcript and the mutant protein were both highly expressed, and despite the location of the insertion into the metal ion-binding loop IV, the SOD1 activity appeared high. In erythrocytes, which lack protein synthesis and are old compared with cultured fibroblasts, both SOD1 protein and enzymic activity was 50% of controls. Thus, the usage of the novel splice site is near 100%, and the mutant SOD1 shows the reduced stability typical of ALS-associated mutant SOD1s. The findings suggests that this novel intronic mutation is causing the disease and highlights the importance of wide exon-flanking sequencing and transcript analysis combined with erythrocyte SOD1 activity analysis in comprehensive search for SOD1 mutations in ALS. We find that there are potentially more SOD1 mutations than previously reported.

  • 17. Blain, C R V
    et al.
    Brunton, S
    Williams, V C
    Leemans, A
    Turner, M R
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Catani, M
    Stanton, B R
    Ganesalingham, J
    Jones, D K
    Williams, S C R
    Leigh, P N
    Simmons, A
    Differential corticospinal tract degeneration in homozygous 'D90A' SOD-1 ALS and sporadic ALS2011In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 82, no 8, p. 843-849Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis.

    METHOD: 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using 'upper motor neuron burden,' El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length.

    RESULTS: Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls.

    CONCLUSIONS: Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients.

  • 18. Blasco, Helene
    et al.
    Bernard-Marissal, Nathalie
    Vourc'h, Patrick
    Guettard, Yves Olivier
    Sunyach, Claire
    Augereau, Olivier
    Khederchah, Joelle
    Mouzat, Kevin
    Antar, Catherine
    Gordon, Paul H.
    Veyrat-Durebex, Charlotte
    Besson, Gerard
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Salachas, Francois
    Meininger, Vincent
    Camu, William
    Pettmann, Brigitte
    Andres, Christian R.
    Corcia, Philippe
    A Rare Motor Neuron Deleterious Missense Mutation in the DPYSL3 (CRMP4) Gene is Associated with ALS2013In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 34, no 7, p. 953-960Article in journal (Refereed)
    Abstract [en]

    The dihydropyrimidinase-like 3 (DPYSL3) or Collapsin Response Mediator Protein 4a (CRMP4a) expression is modified in neurodegeneration and is involved in several ALS-associated pathways including axonal transport, glutamate excitotoxicity, and oxidative stress. The objective of the study was to analyze CRMP4 as a risk factor for ALS. We analyzed the DPYSL3/CRMP4 gene in French ALS patients (n=468) and matched-controls (n=394). We subsequently examined a variant in a Swedish population (184 SALS, 186 controls), and evaluated its functional effects on axonal growth and survival in motor neuron cell culture. The rs147541241:A>G missense mutation occurred in higher frequency among French ALS patients (odds ratio=2.99) but the association was not confirmed in the Swedish population. In vitro expression of mutated DPYSL3 in motor neurons reduced axonal growth and accelerated cell death compared with wild type protein. Thus, the association between the rs147541241 variant and ALS was limited to the French population, highlighting the geographic particularities of genetic influences (risks, contributors). The identified variant appears to shorten motor neuron survival through a detrimental effect on axonal growth and CRMP4 could act as a key unifier in transduction pathways leading to neurodegeneration through effects on early axon development.

  • 19. Blauw, Hylke M
    et al.
    Al-Chalabi, Ammar
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    van Vught, Paul W J
    Diekstra, Frank P
    van Es, Michael A
    Saris, Christiaan G J
    Groen, Ewout J N
    van Rheenen, Wouter
    Koppers, Max
    Van't Slot, Ruben
    Strengman, Eric
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G
    Kiemeney, Lambertus A
    Vermeulen, Sita H M
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Waibel, Stefan
    Meyer, Thomas
    Cronin, Simon
    McLaughlin, Russell L
    Hardiman, Orla
    Sapp, Peter C
    Tobin, Martin D
    Wain, Louise V
    Tomik, Barbara
    Slowik, Agnieszka
    Lemmens, Robin
    Rujescu, Dan
    Schulte, Claudia
    Gasser, Thomas
    Brown, Robert H
    Landers, John E
    Robberecht, Wim
    Ludolph, Albert C
    Ophoff, Roel A
    Veldink, Jan H
    van den Berg, Leonard H
    A large genome scan for rare CNVs in amyotrophic lateral sclerosis2010In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 19, no 20, p. 4091-4099Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.

  • 20. Blumen, Sergiu C
    et al.
    Inzelberg, Rivka
    Nisipeanu, Puiu
    Carasso, Ralph L
    Oved, Daniel
    Aizenstein, Orna
    Drory, Vivian E
    Bergstrom, Christina
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Aggressive familial ALS with unusual brain MRI and a SOD1 gene mutation.2010In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 11, no 1-2, p. 228-231Article in journal (Refereed)
    Abstract [en]

    We studied two sisters with rapidly progressing ALS starting at the ages of 46 and 48 years and leading to death after 14 months. Both fulfilled the El Escorial criteria for definite ALS and had marked upper motor neuron (UMN) predominance. Brain MRI, on fluid attenuation recovery (FLAIR) mode, showed outstanding hyperintensities of the precentral gyrus, centrum semiovale, corona radiata and along the corticospinal pathways in the brainstem. Screening for the SOD1 gene disclosed, at codon 140, a base substitution of adenine for thymine (GGT>CCA) known as the A140A 'silent' mutation since it does not change the amino acid (alanine) encoded for at that position. The severe UMN involvement and the fast progression of the disease may correlate with the MRI findings. It is also possible that the A140A mutation is not incidental; the mutated mRNA might be cytotoxic.

  • 21. Bogaert, Elke
    et al.
    Goris, An
    Van Damme, Philip
    Geelen, Veerle
    Lemmens, Robin
    van Es, Michael A
    van den Berg, Leonard H
    Sleegers, Kristel
    Verpoorten, Nathalie
    Timmerman, Vincent
    Jonghe, Peter De
    Van Broeckhoven, Christine
    Traynor, Bryan J
    Landers, John E
    Brown, Robert H
    Glass, Jonathan D
    Al-Chalabi, Ammar
    Shaw, Christopher E
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Slowik, Agnieszka
    Tomik, Barbara
    Melki, Judith
    Robberecht, Wim
    Van Den Bosch, Ludo
    Polymorphisms in the GluR2 gene are not associated with amyotrophic lateral sclerosis2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 2, p. 418-420Article in journal (Refereed)
    Abstract [en]

    Excitotoxicity is thought to play a pathogenic role in amyotrophic lateral sclerosis (ALS). Excitotoxic motor neuron death is mediated through the Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type of glutamate receptors and Ca(2+) permeability is determined by the GluR2 subunit. We investigated whether polymorphisms or mutations in the GluR2 gene (GRIA2) predispose patients to ALS. Upon sequencing 24 patients and 24 controls no nonsynonymous coding variants were observed but 24 polymorphisms were identified, 9 of which were novel. In a screening set of 310 Belgian ALS cases and 794 healthy controls and a replication set of 3157 cases and 5397 controls from 6 additional populations no association with susceptibility, age at onset, or disease duration was observed. We conclude that polymorphisms in the GluR2 gene (GRIA2) are not a major contributory factor in the pathogenesis of ALS.

  • 22. Broom, Wendy J
    et al.
    Johnson, D V
    Auwarter, K E
    Iafrate, A J
    Russ, C
    Al-Chalabi, A
    Sapp, P C
    McKenna-Yasek, D
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Brown, R H
    SOD1A4V-mediated ALS: absence of a closely linked modifier gene and origination in Asia2008In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 430, no 3, p. 241-245Article in journal (Refereed)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1(A4V) is the most common SOD1 mutation. Carriers of the SOD1(A4V) mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3-5 years with other dominant SOD1 mutations). Previous studies of SOD1(A4V) carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1(A4V) patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1(A4V)-mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1(A4V) ALS to 2.8Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1(A4V) patients. It therefore appears likely that the aggressive nature of the SOD1(A4V) mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (approximately 12,000 years) ago (95% CI 480-700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian-Americans who reached the Americas through the Bering Strait.

  • 23. Broom, Wendy J
    et al.
    Johnson, Daniel V
    Garber, Manuel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Lennon, Niall
    Landers, John
    Nusbaum, Chad
    Russ, Carsten
    Brown, Robert H
    DNA sequence analysis of the conserved region around the SOD1 gene locus in recessively inherited ALS2009In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 463, no 1, p. 64-69Article in journal (Refereed)
    Abstract [en]

    Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; 12-23% are associated with mutations in the Cu/Zn superoxide dismutase gene (SOD1). All ALS-linked SOD1 mutations present with a dominant pattern of inheritance apart from the aspartate to alanine mutation in exon 4 (D90A). This mutation has been observed in dominant, recessive and apparently sporadically cases. SOD1(D90A/D90A) ALS cases have a very slow disease progression (>10 years), raising the hypothesis that modifier genes linked to SOD1 ameliorate the phenotype of recessively inherited SOD1(D90A/D90A) mutations. Previous sequence analysis of a conserved haplotype region around the SOD1 gene did not reveal any functional polymorphisms within known coding or putative regulatory regions. In the current study we expanded the previous analyses by sequencing the entire SOD1 conserved haplotypic region. Although many polymorphisms were identified, none of these variants explain the slowly progressive phenotype observed in patients with recessive SOD1(D90A) mutations. This study disproves the hypothesis that there is a tightly linked genetic protective factor specifically located close to the SOD1 gene in SOD1(D90A) mediated ALS.

  • 24. Brotherton, Terrell
    et al.
    Polak, Meraida
    Kelly, Crystal
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Glass, Jonathan D
    A novel ALS SOD1 C6S mutation with implications for aggregation related toxicity and genetic counseling2011In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 12, no 3, p. 215-219Article in journal (Refereed)
    Abstract [en]

    In this report we describe an ALS family with a novel missense SOD1 mutation with substitution of serine for cysteine at the sixth amino acid (C6S). This mutation has interesting implications for the role of disulfides in causing disease. After identification of the ALS proband, we examined 17 members of an extended family and performed DNA mutation analysis on 21 family members. The level and activity of SOD1 in C6S carriers and wild-type family members was analyzed in erythrocytes. We found that the C6S mutation results in disease with an autosomal dominant mode of inheritance and markedly reduced penetrance. The S6 mutated protein demonstrates high stability relative to the C6 wild-type protein. The specific dismutation activity of S6 SOD1 is normal. In conclusion, C6S is a novel FALS associated mutation with reduced disease penetrance, long survival time and a phenotype very different from the other SOD1 mutations reported in codon C6. This mutation may provide insight into the role of SOD1 structural changes in disease.

  • 25. Burgunder, J-M
    et al.
    Schöls, L
    Baets, J
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Gasser, T
    Szolnoki, Z
    Fontaine, B
    Van Broeckhoven, C
    Di Donato, S
    De Jonghe, P
    Lynch, T
    Mariotti, C
    Spinazzola, A
    Tabrizi, S J
    Tallaksen, C
    Zeviani, M
    Harbo, H F
    Finsterer, J
    EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders2011In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 18, no 2, p. 207-E20Article in journal (Refereed)
    Abstract [en]

    Objectives: These EFNS guidelines on the molecular diagnosis of motoneuron disorders, neuropathies and myopathies are designed to summarize the possibilities and limitations of molecular genetic techniques and to provide diagnostic criteria for deciding when a molecular diagnostic work-up is indicated. Search strategy: To collect data about planning, conditions and performance of molecular diagnosis of these disorders, a literature search in various electronic databases was carried out and original papers, meta-analyses, review papers and guideline recommendations reviewed. Results: The best level of evidence for genetic testing recommendation (B) can be found for the disorders with specific presentations, including familial amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, Charcot-Marie-Tooth 1A, myotonic dystrophy and Duchenne muscular dystrophy. For a number of less common disorders, a precise description of the phenotype, including the use of immunologic methods in the case of myopathies, is considered as good clinical practice to guide molecular genetic testing. Conclusion: These guidelines are provisional and the future availability of molecular-genetic epidemiological data about the neurogenetic disorders under discussion in this article will allow improved recommendation with an increased level of evidence.

  • 26.
    Byström, Roberth
    et al.
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Oliveberg, Mikael
    Stockholms universitet.
    SOD1 mutations targeting surface hydrogen bonds promote ALS without reducing apo-state stability2010In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 285, no 25, p. 19544-52Article in journal (Refereed)
    Abstract [en]

    In good accord with the protein-aggregation hypothesis for neurodegenerative diseases, ALS-associated SOD1 mutations are found to reduce structural stability or net repulsive charge. Moreover there are weak indications that the ALS disease progression rate is correlated with the degree of mutational impact on the apo-SOD1 structure. A bottleneck for obtaining more conclusive information about these structure-disease relationships, however, is the large intrinsic variability in patient survival times and insufficient disease statistics for the majority of ALS-provoking mutations. As an alternative test of the structure-disease relationship we focus here on the SOD1 mutations that appear to be outliers in the data set. The results identify several ALS-provoking mutations whose only effect on apo SOD1 is the elimination or introduction of a single charge, i.e., D76V/Y, D101N and N139D/K. The thermodynamic stability and folding behaviour of these mutants are indistinguishable from the wildtype control. Moreover, D101N is an outlier in the plot of stability loss vs. patient survival time by having rapid disease progression. Common to the identified mutations is that they truncate conserved salt-links and/or H-bond networks in the functional loops IV or VII. The results show that the local impact of ALS-associated mutations on the SOD1 molecule can sometimes overrun their global effects on apo-state stability and net repulsive charge, and point at the analysis of property outliers as an efficient strategy for mapping out new ALS-provoking features.

  • 27.
    Byström, Roberth
    et al.
    Umeå University, Faculty of Science and Technology, Chemistry.
    Andersen, Peter Munch
    Umeå University, Faculty of Medicine, Pharmacology and Clinical Neuroscience, Neurology.
    Gröbner, Gerhard
    Umeå University, Faculty of Science and Technology, Chemistry.
    Oliveberg, Mikael
    Department of Biochemistry and Biophysics, Arrhenius Laboratories of Natural Sciences, Stockholm University, S-106 91 Stockholm, Sweden.
    Identification of property outliers among ALS-associated SOD1 mutations: Common effect on surface hydrogen bondsManuscript (preprint) (Other (popular science, discussion, etc.))
    Abstract [en]

    In good accord with the protein-aggregation hypothesis for neurodegenerative diseaseALS-associated SOD1 mutations are found to reduce structural stability or netrepulsive charge. Moreover there are weak indications that the ALS diseaseprogression is correlated with the degree of mutational impact on the SOD1 structure.A bottleneck for obtaining more conclusive information about these structure-diseaserelationships, however, is the large intrinsic variability in patient survival times andinsufficient disease statistics for the majority of ALS-provoking mutations. As analternative test of the structure-disease relationship we focus here on the SOD1 amutation that appears to be outliers in the data set. The results identify several ALSprovokingmutations whose only effect on apo SOD1 is the elimination orintroduction of a single charge, i.e., D76V/Y, D101N and N139D/K. Thethermodynamic stability and folding behaviour of these mutants are indistinguishablefrom the wildtype control, showing that structurally benign replacements of individualsurface charges are sufficient to trigger ALS. Moreover, D101N is a clear outlier inthe plot of stability loss vs. patient survival time by having too rapid diseaseprogression. Common to the identified mutations is that they truncate conserved saltlinksand/or H-bond networks in the functional loops IV or VII. The results show thatthe local impact of ALS-associated mutations on the SOD1 molecule can sometimesoverrun their global effects on stability and net repulsive charge, and point at theanalysis of property outliers as an efficient strategy for mapping out new ALSprovokingfeatures.

  • 28. Carew, J. D.
    et al.
    Nair, G.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    Wuu, J.
    Gronka, S.
    Hu, X.
    Benatar, M.
    Presymptomatic spinal cord neurometabolic findings in SOD1-positive people at risk for familial ALS2011In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 77, no 14, p. 1370-1375Article in journal (Refereed)
    Abstract [en]

    Objectives: It has been speculated that amyotrophic lateral sclerosis (ALS) is characterized by a premanifest period during which neurodegeneration precedes the appearance of clinical manifestations. Magnetic resonance spectroscopy (MRS) was used to measure rations of neurometabolites in the cervical spine of asymptomatic individuals with a mutation in the SOD1 gene (SOD1+) and compare their neurometabolic ratios to patients with ALS and healthy controls.

    Methods: A cross-sectional study of (1)H-MRS of the cervical spine was performed on 24 presymptomatic SOD1+ volunteers, 29 healthy controls, and 23 patients with ALS. All presymptomatic subjects had no symptoms of disease, normal forced vital capacity, and normal electromyographic examination. Relative concentrations of choline (Cho), creatine (Cr), myo-inositol (Myo), and N-acetylasparate (NAA) were determined.

    Results: NAA/Cr and NAA/Myo rations are reduced in both SOD1+ subjects (39.7%, p = 0.001 and 18.0%, p = 0.02) and patients with ALS (41.2%, p < 0.001 and 24.0%, p = 0.01) compared to controls. Myo/Cr is reduced (10.3%, p = 0.02) in SOD1+ subjects compared to controls, but no difference was found between patients with ALS and controls. By contrast, NAA/Cho is reduced in patients with ALS (24.0%, p = 0.002), but not in presymptomatic SOD1+ subjects compared to controls.

    Conclusions: Changes in neurometabolite ratios in the cervical spinal cord are evident in presymptomatic SOD1+ individuals in advance of symptoms and clinical or electromyographic changes in this population resemble changes observed in patients with clinically apparent ALS. This suggest that neurometabolic changed occur early in the course of the disease process.

  • 29. Chiang, Huei-Hsin
    et al.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Tysnes, Ole-Bjørn
    Gredal, Ole
    Christensen, Peter B
    Graff, Caroline
    Novel TARDBP mutations in Nordic ALS patients2012In: Journal of Human Genetics, ISSN 1434-5161, E-ISSN 1435-232X, Vol. 57, no 5, p. 316-319Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a neurodegenerative syndrome primarily affecting the upper and lower motor neurons. A characteristic neuropathological finding in ALS patients is neuronal inclusions positive for TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the gene encoding TDP-43, TARDBP, proved to be involved in the development of ALS. We thus sequenced TARDBP in 177 Nordic ALS patients and found two previously reported (p.A90V and p.S379P) and two novel (p.G357R and p.R361T) missense variations in three familial ALS patients. The p.A90V and p.G357R variations were detected in the same patient and p.R361T was present in a family with both ALS and frontotemporal dementia-ALS. None of the missense variations were present in 200 neurologically healthy controls. However, p.A90V has also been reported in healthy individuals by others. Thus, the data suggest that these variations are rare and p.G357R, p.R361T and p.S379P are likely pathogenic but further functional characterization is needed to prove their pathogenicity. The mutation frequency in TARDBP in Nordic ALS patients was 1.7%. The ALS cohort was highly selected for a positive family history suggesting that mutations in TARDBP generally are a rare cause of ALS in Nordic countries.

  • 30. Corcia, Philippe
    et al.
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Blasco, Helene
    Press, Rayomand
    Praline, Julien
    Antar, Catherine
    Veyrat-Durebex, Charlotte
    Guettard, Yves-Olivier
    Camu, William
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Vourc'h, Patrick
    Andres, Christian R
    Homozygous SMN2 deletion is a protective factor in the Swedish ALS population2012In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 20, no 5, p. 588-591Article in journal (Refereed)
    Abstract [en]

    Abnormal survival motor neuron 1 (SMN1)-copy number has been associated with an increased risk of amyotrophic lateral sclerosis (ALS) in French and Dutch population studies. The aim of this study was to determine whether SMN gene copy number increases the risk of ALS or modulates its phenotype in a cohort of Swedish sporadic ALS (SALS) patients. In all, 502 Swedes with SALS and 502 Swedish controls matched for gender and age were enrolled. SMN1 and SMN2 gene copy numbers were studied by a semi-quantitative PCR method. A genotype-phenotype comparison was performed in order to determine whether SMN genes modulate the phenotype of ALS. The results were also compared with our previously reported French cohort of ALS patients. There was no difference between Swedish patients and controls in the frequency of SMN1 and SMN2 copy numbers. The frequency of SMN1 gene copies differed significantly between the French and Swedish ALS populations. The duration of the disease was significantly longer in the Swedish cohort with homozygous deletions of SMN2 when compared with the French cohort. Abnormal SMN1 gene copy number cannot be considered as a universal genetic susceptibility factor for SALS and this result underlines the importance of reproducing association gene studies in groups from different origins. We also suggest that SMN2 gene copy number might have different effects on ALS progression in disparate human populations. European Journal of Human Genetics (2012) 20, 588-591; doi:10.1038/ejhg.2011.255; published online 25 January 2012

  • 31. Couthouis, Julien
    et al.
    Hart, Michael P
    Shorter, James
    DeJesus-Hernandez, Mariely
    Erion, Renske
    Oristano, Rachel
    Liu, Annie X
    Ramos, Daniel
    Jethava, Niti
    Hosangadi, Divya
    Epstein, James
    Chiang, Ashley
    Diaz, Zamia
    Nakaya, Tadashi
    Ibrahim, Fadia
    Kim, Hyung-Jun
    Solski, Jennifer A
    Williams, Kelly L
    Mojsilovic-Petrovic, Jelena
    Ingre, Caroline
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Boylan, Kevin
    Graff-Radford, Neill R
    Dickson, Dennis W
    Clay-Falcone, Dana
    Elman, Lauren
    McCluskey, Leo
    Greene, Robert
    Kalb, Robert G
    Lee, Virginia M-Y
    Trojanowski, John Q
    Ludolph, Albert
    Robberecht, Wim
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Nicholson, Garth A
    Blair, Ian P
    King, Oliver D
    Bonini, Nancy M
    Van Deerlin, Vivianna
    Rademakers, Rosa
    Mourelatos, Zissimos
    Gitler, Aaron D
    A yeast functional screen predicts new candidate ALS disease genes2011In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 108, no 52, p. 20881-20890Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating and universally fatal neurodegenerative disease. Mutations in two related RNA-binding proteins, TDP-43 and FUS, that harbor prion-like domains, cause some forms of ALS. There are at least 213 human proteins harboring RNA recognition motifs, including FUS and TDP-43, raising the possibility that additional RNA-binding proteins might contribute to ALS pathogenesis. We performed a systematic survey of these proteins to find additional candidates similar to TDP-43 and FUS, followed by bioinformatics to predict prion-like domains in a subset of them. We sequenced one of the segenes, TAF15, in patients with ALS and identified missense variants, which were absent in a large number of healthy controls. These disease-associated variants of TAF15 caused formation of cytoplasmic foci when expressed in primary cultures of spinal cord neurons. Very similar to TDP-43 and FUS, TAF15 aggregated in vitro and conferred neurodegeneration in Drosophila, with the ALS-linked variants having amore severe effect than wild type. Immunohistochemistry of postmortem spinal cord tissue revealed mislocalization of TAF15 in motor neurons of patients with ALS. We propose that aggregation-prone RNA-binding proteins might contribute very broadly to ALS pathogenesis and the genes identified in our yeast functional screen, coupled with prion-like domain prediction analysis, now provide a powerful resource to facilitate ALS disease gene discovery.

  • 32. Cronin, Simon
    et al.
    Greenway, Matthew J
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Hardiman, Orla
    Screening of hypoxia-inducible genes in sporadic ALS2008In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 9, no 5, p. 299-305Article in journal (Refereed)
    Abstract [en]

    Genetic variations in two hypoxia-inducible angiogenic genes, VEGF and ANG, have been linked with sporadic amyotrophic lateral sclerosis (SALS). Common variations in these genes may reduce the levels or functioning of their products. VEGF and ANG belong to a larger group of angiogenic genes that are up-regulated under hypoxic conditions. We hypothesized that common genetic variation across other members of this group may also predispose to sporadic ALS. To screen other hypoxia-inducible angiogenic genes for association with SALS, we selected 112 tagging single nucleotide polymorphisms (tgSNPs) that captured the common genetic variation across 16 VEGF-like and eight ANG-like hypoxia-inducible genes. Screening for association was performed in 270 Irish individuals with typical SALS and 272 ethnically matched unrelated controls. SNPs showing association in the Irish phase were genotyped in a replication sample of 281 Swedish sporadic ALS patients and 286 Swedish controls. Seven markers showed association in the Irish. The one modest replication signal observed in the Swedish replication sample, at rs3801158 in the gene inhibin beta A, was for the opposite allele vs. the Irish cohort. We failed to detect association of common variation across 24 candidate hypoxia-inducible angiogenic genes with SALS.

  • 33. Czell, D.
    et al.
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Morita, M.
    Neuwirth, C.
    Perren, F.
    Weber, M.
    Phenotypes in Swiss Patients with Familial ALS Carrying TARDBP Mutations2013In: Neurodegenerative Diseases, ISSN 1660-2854, Vol. 12, no 3, p. 150-155Article in journal (Refereed)
    Abstract [en]

    Background: Recently, mutations in the TARDBP gene encoding the TAR DNA-binding protein 43 (TDP-43) have been identified in some familial annyotrophic lateral sclerosis (ALS) and sporadic ALS patients. The phenotype and frequency of TARDBP mutation carriers reportedly varies greatly among European populations. Objective: To define the phenotypic spectrum of TARDBP mutations and their frequency in a Swiss population. Methods: A total of 225 patients diagnosed with ALS (182 sporadic cases, 43 familial cases) were screened for TARDBP mutations. All patients were carefully examined and interviewed for a familial predisposition. Except for 1 patient who was followed at the University of Geneva, all patients were followed at the Kantonsspital St. Gallen. Results: 43 patients (19.5%) had a definite family history for ALS. A TARDBP mutation was identified in 4 of these (9.3%). Two female ALS patients carried the p.Asn352Ser mutation. Both had limb onset and a slowly progressive course of the disease. A novel mutation (p.Gly376Asp) was identified in a 44-year-old female patient. Survival amongst affected family members varied between 6 and 18 months. The patient and also the other siblings affected with ALS had an accessory nipple. A fourth male patient carried the p.Ala-90Val mutation. None of the patients had overt cognitive impairment. TARDBP mutations were not found among patients with sporadic forms of ALS. Conclusion: In this Swiss population, the frequency of familial ALS is higher than reported earlier in other populations. The novel p.Gly376Asp TARDBP mutation is associated with rapid disease progression and may be associated with an accessory nipple while the p.Asn352Ser mutation is associated with slow disease progression.

  • 34.
    Czell, David
    et al.
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Neuwirth, Christoph
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Morita, Mitsuya
    Jichi Med Univ, Dept Neurol, Shimotsuke, Japan.
    Weber, Markus
    Kantonsspital, Neuromuscular Dis Unit, ALS Clin, CH-9007 St Gallen, Switzerland.
    Progressive aphasia as the presenting symptom in a patient with amyotrophic lateral sclerosis with a novel mutation in the OPTN gene2013In: Amyotrophic Lateral Sclerosis and Frontootemporal Degeneration, ISSN 2167-8421, Vol. 14, no 2, p. 138-140Article in journal (Refereed)
  • 35. Deng, Min
    et al.
    Wei, Ling
    Zuo, Xianbo
    Tian, Yanghua
    Xie, Fei
    Hu, Panpan
    Zhu, Chunyan
    Yu, Fengqiong
    Meng, Yu
    Wang, Honghao
    Zhang, Fangfang
    Ma, Huijuan
    Ye, Rong
    Cheng, Huaidong
    Du, Jing
    Dong, Wenwen
    Zhou, Shanshan
    Wang, Changqing
    Wang, Yu
    Wang, Jingye
    Chen, Xianwen
    Sun, Zhongwu
    Zhou, Nong
    Jiang, Yubao
    Liu, Xiuxiu
    Li, Xiaogang
    Zhang, Nan
    Liu, Na
    Guan, Yingjun
    Han, Yongsheng
    Han, Yongzhu
    Lv, Xinyi
    Fu, Yu
    Yu, Hui
    Xi, Chunhua
    Xie, Dandan
    Zhao, Qiyuan
    Xie, Peng
    Wang, Xin
    Zhang, Zhijun
    Shen, Lu
    Cui, Yong
    Yin, Xianyong
    Cheng, Hui
    Liang, Bo
    Zheng, Xiaodong
    Lee, Tatia M. C.
    Chen, Gang
    Zhou, Fusheng
    Veldink, Jan H.
    Robberecht, Wim
    Landers, John E.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Al-Chalabi, Ammar
    Shaw, Chris
    Liu, Chunfeng
    Tang, Beisha
    Xiao, Shangxi
    Robertson, Janice
    Zhang, Fengyu
    van den Berg, Leonard H.
    Sun, Liangdan
    Liu, Jianjun
    Yang, Sen
    Ju, Xiaodong
    Wang, Kai
    Zhang, Xuejun
    Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis2013In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 6, p. 697-+Article in journal (Refereed)
    Abstract [en]

    To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.

  • 36. Diekstra, Frank P.
    et al.
    Saris, Christiaan G. J.
    van Rheenen, Wouter
    Franke, Lude
    Jansen, Ritsert C.
    van Es, Michael A.
    van Vught, Paul W. J.
    Blauw, Hylke M.
    Groen, Ewout J. N.
    Horvath, Steve
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    Robberecht, Wim
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Al-Chalabi, Ammar
    Ophoff, Roel A.
    van den Berg, Leonard H.
    Veldink, Jan H.
    Mapping of Gene Expression Reveals CYP27A1 as a Susceptibility Gene for Sporadic ALS2012In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e35333-Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by loss of upper and lower motor neurons. ALS is considered to be a complex trait and genome-wide association studies (GWAS) have implicated a few susceptibility loci. However, many more causal loci remain to be discovered. Since it has been shown that genetic variants associated with complex traits are more likely to be eQTLs than frequency-matched variants from GWAS platforms, we conducted a two-stage genome-wide screening for eQTLs associated with ALS. In addition, we applied an eQTL analysis to finemap association loci. Expression profiles using peripheral blood of 323 sporadic ALS patients and 413 controls were mapped to genome-wide genotyping data. Subsequently, data from a two-stage GWAS (3,568 patients and 10,163 controls) were used to prioritize eQTLs identified in the first stage (162 ALS, 207 controls). These prioritized eQTLs were carried forward to the second sample with both gene-expression and genotyping data (161 ALS, 206 controls). Replicated eQTL SNPs were then tested for association in the second-stage GWAS data to find SNPs associated with disease, that survived correction for multiple testing. We thus identified twelve cis eQTLs with nominally significant associations in the second-stage GWAS data. Eight SNP-transcript pairs of highest significance (lowest p = 1.27 x 10(-51)) withstood multiple-testing correction in the second stage and modulated CYP27A1 gene expression. Additionally, we show that C9orf72 appears to be the only gene in the 9p21.2 locus that is regulated in cis, showing the potential of this approach in identifying causative genes in association loci in ALS. This study has identified candidate genes for sporadic ALS, most notably CYP27A1. Mutations in CYP27A1 are causal to cerebrotendinous xanthomatosis which can present as a clinical mimic of ALS with progressive upper motor neuron loss, making it a plausible susceptibility gene for ALS.

  • 37. Diekstra, Frank P.
    et al.
    Van Deerlin, Vivianna M.
    van Swieten, John C.
    Al-Chalabi, Ammar
    Ludolph, Albert C.
    Weishaupt, Jochen H.
    Hardiman, Orla
    Landers, John E.
    Brown, Robert H., Jr.
    van Es, Michael A.
    Pasterkamp, R. Jeroen
    Koppers, Max
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Estrada, Karol
    Rivadeneira, Fernando
    Hofman, Albert
    Uitterlinden, Andre G.
    van Damme, Philip
    Melki, Judith
    Meininger, Vincent
    Shatunov, Aleksey
    Shaw, Christopher E.
    Leigh, P. Nigel
    Shaw, Pamela J.
    Morrison, Karen E.
    Fogh, Isabella
    Chio, Adriano
    Traynor, Bryan J.
    Czell, David
    Weber, Markus
    Heutink, Peter
    de Bakker, Paul I. W.
    Silani, Vincenzo
    Robberecht, Wim
    van den Berg, Leonard H.
    Veldink, Jan H.
    C9orf72 and UNC13A Are Shared Risk Loci for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia: A Genome-Wide Meta-Analysis2014In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 76, no 1, p. 120-133Article in journal (Refereed)
    Abstract [en]

    Objective: Substantial clinical, pathological, and genetic overlap exists between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 inclusions have been found in both ALS and FTD cases (FTD-TDP). Recently, a repeat expansion in C9orf72 was identified as the causal variant in a proportion of ALS and FTD cases. We sought to identify additional evidence for a common genetic basis for the spectrum of ALS-FTD. Methods: We used published genome-wide association studies data for 4,377 ALS patients and 13,017 controls, and 435 pathology-proven FTD-TDP cases and 1,414 controls for genotype imputation. Data were analyzed in a joint meta-analysis, by replicating topmost associated hits of one disease in the other, and by using a conservative rank products analysis, allocating equal weight to ALS and FTD-TDP sample sizes. Results: Meta-analysis identified 19 genome-wide significant single nucleotide polymorphisms (SNPs) in C9orf72 on chromosome 9p21.2 (lowest p = 2.6 x 10(-12)) and 1 SNP in UNC13A on chromosome 19p13.11 (p = 1.0 x 10(-11)) as shared susceptibility loci for ALS and FTD-TDP. Conditioning on the 9p21.2 genotype increased statistical significance at UNC13A. A third signal, on chromosome 8q24.13 at the SPG8 locus coding for strumpellin (p = 3.91 x 10(-7)) was replicated in an independent cohort of 4,056 ALS patients and 3,958 controls (p = 0.026; combined analysis p = 1.01 x 10(-7)). Interpretation: We identified common genetic variants in C9orf72, but in addition in UNC13A that are shared between ALS and FTD. UNC13A provides a novel link between ALS and FTD-TDP, and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP.

  • 38. Diekstra, Frank P.
    et al.
    van Vught, Paul W. J.
    van Rheenen, Wouter
    Koppers, Max
    Pasterkamp, R. Jeroen
    van Es, Michael A.
    Schelhaas, Helenius J.
    de Visser, Marianne
    Robberecht, Wim
    van Damme, Philip
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience.
    van den Berg, Leonard H.
    Veldink, Jan H.
    UNC13A is a modifier of survival in amyotrophic lateral sclerosis2012In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 33, no 3, p. 630.e3-630.e8Article in journal (Refereed)
    Abstract [en]

    A large genome-wide screen in patients with sporadic amyotrophic lateral sclerosis (ALS) showed that the common variant rs12608932 in gene UNC13A was associated with disease susceptibility. UNC13A regulates the release of neurotransmitters, including glutamate. Genetic risk factors that, in addition, modify survival, provide promising therapeutic targets in ALS, a disease whose etiology remains largely elusive. We examined whether UNC13A was associated with survival of ALS patients in a cohort of 450 sporadic ALS patients and 524 unaffected controls from a population-based study of ALS in The Netherlands. Additionally, survival data were collected from individuals of Dutch, Belgian, or Swedish descent (1767 cases, 1817 controls) who had participated in a previously published genome-wide association study of ALS. We related survival to rs12608932 genotype. In both cohorts, the minor allele of rs12608932 in UNC13A was not only associated with susceptibility but also with shorter survival of ALS patients. Our results further corroborate the role of UNC13A in ALS pathogenesis. (C) 2012 Elsevier Inc. All rights reserved.

  • 39. Eisen, Andrew
    et al.
    Mezei, Michelle M
    Stewart, Heather G
    Fabros, Marife
    Gibson, Gillan
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    SOD1 gene mutations in ALS patients from British Columbia, Canada: clinical features, neurophysiology and ethical issues in management2008In: Amyotrophic Lateral Sclerosis and other Motor Neuron Disorders, ISSN 1466-0822, E-ISSN 1743-4483, Vol. 9, no 2, p. 108-119Article in journal (Refereed)
    Abstract [en]

    Two hundred and fifty-four ALS patients from British Columbia, Canada were screened for mutations in the gene encoding the enzyme superoxide dismutase type 1 (SOD1). Thirteen patients (5.1%) carried one of six missense mutations (A4V, G72C, D76Y, D90A, C111Y, I113T). Mutations were found both in sporadic and familial ALS cases. Atypical clinical features delayed diagnosis in some cases. The demographic and clinical features of the mutation carrying index cases are summarized, and compared with those of screened patients without mutations. The phenotypic variability between SOD1 mutation carrying patients in this study is dramatic, even among patients with the same mutation This underlines the hypothesis that ALS is a biologically heterogeneous disorder in which genetics, environment and ageing all interrelate to form the final clinical phenotype.

  • 40.
    Eschbach, Judith
    et al.
    Neurology, Ulm University, Germany.
    Schwalenstocker, Birgit
    Neurology, Ulm University, Germany.
    Soyal, Selma M.
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Bayer, Hanna
    Neurology, Ulm University, Germany.
    Wiesner, Diana
    Neurology, Ulm University, Germany.
    Akimoto, Chizuru
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Nilsson, Ann-Charloth
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Birve, Anna
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Meyer, Thomas
    Neurology, Charité University Hospital, Berlin, Germany.
    Dupuis, Luc
    INSERM, Strasbourg, France ; Faculté de Médecine, Université de Strasbourg, , France.
    Danzer, Karin M.
    Neurology, Ulm University, Germany.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Neurology, Ulm University, Germany.
    Witting, Anke
    Neurology, Ulm University, Germany.
    Ludolph, Albert C.
    Neurology, Ulm University, Germany.
    Patsch, Wolfgang
    Pharmacology, Paracelsus Medical University, Salzburg, Austria.
    Weydt, Patrick
    Neurology, Ulm University, Germany.
    PGC-1 is a male-specific disease modifier of human and experimental amyotrophic lateral sclerosis2013In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 22, no 17, p. 3477-3484Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.

  • 41. Fanos, Joanna H
    et al.
    Gronka, Susan
    Wuu, Joanne
    Stanislaw, Christine
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Benatar, Michael
    Impact of presymptomatic genetic testing for familial amyotrophic lateral sclerosis2011In: Genetics in Medicine, ISSN 1098-3600, E-ISSN 1530-0366, Vol. 13, no 4, p. 342-348Article in journal (Refereed)
    Abstract [en]

    PURPOSE: The Pre-familial Amyotrophic Lateral Sclerosis (Pre-fALS) study is a longitudinal study of individuals potentially at risk for developing familial amyotrophic lateral sclerosis. Our goals were to (1) explore participants' decisions of whether to learn results of presymptomatic testing or not; (2) understand the psychosocial impact of these decisions; and (3) assess preferences for receiving results by telephone or in person.

    METHODS: The sample for this substudy comprised 20 participants drawn randomly from autosomal dominant mutant superoxide dismutase 1 families in the Pre-fALS study. Twenty participants completed a semistructured phone interview; prominent themes were identified and rated.

    RESULTS: Fourteen participants chose to learn results; six had mutant superoxide dismutase 1 and eight had wild-type superoxide dismutase 1. Of the six who initially elected nondisclosure, three were reconsidering their decision. Regardless of the results and method of counseling, participants had adapted well, at least in the short term.

    CONCLUSION: We recommend that (1) those considering presymptomatic genetic testing should undergo professional counseling to help decide whether to learn results; (2) discussion should include the option of telephone genetic counseling for those without easy access to in-person counseling; and (3) those who initially decline to learn results should be offered the opportunity to learn their mutation status as their decision evolves.

  • 42. Felbecker, Ansgar
    et al.
    Camu, William
    Valdmanis, Paul N
    Sperfeld, Anne-Dorte
    Waibel, Stefan
    Steinbach, Peter
    Rouleau, Guy A
    Ludolph, Albert C
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Four familial ALS pedigrees discordant for two SOD1 mutations: are all SOD1 mutations pathogenic?2010In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 81, no 5, p. 572-577Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: 153 mutations in the Cu/Zn superoxide dismutase (SOD1) gene have been claimed to be associated with amyotrophic lateral sclerosis (ALS) in familial and sporadic ALS in an autosomal dominant or autosomal recessive pattern with complete or reduced penetrance. The authors now report four ALS pedigrees from Finland, France, Germany and Sweden with either the D90A or E100K SOD1 mutations in some but not all affected members. After re-collecting DNA, the non-segregation of the SOD1 mutations with disease was confirmed by three independent laboratories using different PCR primers: while some of the affected patients carry SOD1 mutations, other affected family members have two wildtype/normal SOD1 genes. In addition, some unaffected members within the same families are carriers of SOD1 gene mutations. To exclude other known genetic causes, the authors ruled out mutations within the genes coding for VAPB, ANG, TDP43, FUS and DCTN1 in affected individuals in the four pedigrees.

    CONCLUSIONS: The authors find that the D90A and E100K SOD1 gene mutations found in some patients are not the exclusive cause of ALS in these pedigrees. Whether this is also the case for the other 151 SOD1 mutations reported in ALS pedigrees is unknown. The findings have consequences for genetic testing in clinical practice when diagnosing ALS and for genetic counselling in ALS. Some SOD1 mutations may be part of an oligo- or epigentic pattern of inheritance. Such a pattern of inheritance may model other oligo- or polygenetic traits responsible for other forms of ALS.

  • 43. Fogh, Isabella
    et al.
    Ratti, Antonia
    Gellera, Cinzia
    Lin, Kuang
    Tiloca, Cinzia
    Moskvina, Valentina
    Corrado, Lucia
    Soraru, Gianni
    Cereda, Cristina
    Corti, Stefania
    Gentilini, Davide
    Calini, Daniela
    Castellotti, Barbara
    Mazzini, Letizia
    Querin, Giorgia
    Gagliardi, Stella
    Del Bo, Roberto
    Conforti, Francesca L.
    Siciliano, Gabriele
    Inghilleri, Maurizio
    Sacca, Francesco
    Bongioanni, Paolo
    Penco, Silvana
    Corbo, Massimo
    Sorbi, Sandro
    Filosto, Massimiliano
    Ferlini, Alessandra
    Di Blasio, Anna M.
    Signorini, Stefano
    Shatunov, Aleksey
    Jones, Ashley
    Shaw, Pamela J.
    Morrison, Karen E.
    Farmer, Anne E.
    Van Damme, Philip
    Robberecht, Wim
    Chi, Adriano
    Traynor, Bryan J.
    Sendtner, Michael
    Melki, Judith
    Meininger, Vincent
    Hardiman, Orla
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Leigh, Nigel P.
    Glass, Jonathan D.
    Overste, Daniel
    Diekstra, Frank P.
    Veldink, Jan H.
    van Es, Michael A.
    Shaw, Christopher E.
    Weale, Michael E.
    Lewis, Cathryn M.
    Williams, Julie
    Brown, Robert H.
    Landers, John E.
    Ticozzi, Nicola
    Ceroni, Mauro
    Pegoraro, Elena
    Comi, Giacomo P.
    DAlfonso, Sandra
    van den Berg, Leonard H.
    Taroni, Franco
    Al-Chalabi, Ammar
    Powell, John
    Silani, Vincenzo
    A genome-wide association meta-analysis identifies a novel locus at 17q11.2 associated with sporadic amyotrophic lateral sclerosis2014In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 23, no 8, p. 2220-2231Article in journal (Refereed)
    Abstract [en]

    Identification of mutations at familial loci for amyotrophic lateral sclerosis (ALS) has provided novel insights into the aetiology of this rapidly progressing fatal neurodegenerative disease. However, genome-wide association studies (GWAS) of the more common (90) sporadic form have been less successful with the exception of the replicated locus at 9p21.2. To identify new loci associated with disease susceptibility, we have established the largest association study in ALS to date and undertaken a GWAS meta-analytical study combining 3959 newly genotyped Italian individuals (1982 cases and 1977 controls) collected by SLAGEN (Italian Consortium for the Genetics of ALS) together with samples from Netherlands, USA, UK, Sweden, Belgium, France, Ireland and Italy collected by ALSGEN (the International Consortium on Amyotrophic Lateral Sclerosis Genetics). We analysed a total of 13 225 individuals, 6100 cases and 7125 controls for almost 7 million single-nucleotide polymorphisms (SNPs). We identified a novel locus with genome-wide significance at 17q11.2 (rs34517613 with P 1.11 10(8); OR 0.82) that was validated when combined with genotype data from a replication cohort (P 8.62 10(9); OR 0.833) of 4656 individuals. Furthermore, we confirmed the previously reported association at 9p21.2 (rs3849943 with P 7.69 10(9); OR 1.16). Finally, we estimated the contribution of common variation to heritability of sporadic ALS as 12 using a linear mixed model accounting for all SNPs. Our results provide an insight into the genetic structure of sporadic ALS, confirming that common variation contributes to risk and that sufficiently powered studies can identify novel susceptibility loci.

  • 44.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Glial nuclear aggregates of superoxide dismutase-1 are regularly present in patients with amyotrophic lateral sclerosis2011In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 121, no 5, p. 623-634Article in journal (Refereed)
    Abstract [en]

    The most common cause of amyotrophic lateral sclerosis (ALS) is mutations in superoxide dismutase-1 (SOD1). Since there is evidence for the involvement of non-neuronal cells in ALS we searched for signs of SOD1 abnormalities focusing on glia. Spinal cords from 9 ALS patients carrying SOD1 mutations, 51 patients with sporadic or familial ALS who lacked such mutations, and 46 controls were examined by immunohistochemistry. A set of anti-peptide antibodies with specificity for misfolded SOD1 species was used. Misfolded SOD1 in the form of granular aggregates was regularly detected in the nuclei of ventral horn astrocytes, microglia and oligodendrocytes in ALS patients carrying and as well as lacking SOD1 mutations. There was negligible staining in neurodegenerative and non-neurological controls. Misfolded SOD1 appeared occasionally also in nuclei of motoneurons of ALS patients. The results suggest that misfolded SOD1 present in glial and motoneuron nuclei may generally be involved in ALS pathogenesis.

  • 45.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Zetterström, Per
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Bergh, Johan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    High expression of wild-type human superoxide dismutase-1 gives a model of sporadic ALSManuscript (preprint) (Other academic)
  • 46.
    Forsberg, Karin
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jonsson, P Andreas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Bergemalm, Daniel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Graffmo, Karin S
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Jacobsson, Johan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Rosquist, Roland
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Marklund, Stefan L
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients2010In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 5, no 7, p. e11552-Article in journal (Refereed)
    Abstract [en]

    Mutations in CuZn-superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS) and are found in 6% of ALS patients. Non-native and aggregation-prone forms of mutant SOD1s are thought to trigger the disease. Two sets of novel antibodies, raised in rabbits and chicken, against peptides spaced along the human SOD1 sequence, were by enzyme-linked immunosorbent assay and an immunocapture method shown to be specific for denatured SOD1. These were used to examine SOD1 in spinal cords of ALS patients lacking mutations in the enzyme. Small granular SOD1-immunoreactive inclusions were found in spinal motoneurons of all 37 sporadic and familial ALS patients studied, but only sparsely in 3 of 28 neurodegenerative and 2 of 19 non-neurological control patients. The granular inclusions were by confocal microscopy found to partly colocalize with markers for lysosomes but not with inclusions containing TAR DNA binding protein-43, ubiquitin or markers for endoplasmic reticulum, autophagosomes or mitochondria. Granular inclusions were also found in carriers of SOD1 mutations and in spinobulbar muscular atrophy (SBMA) patients and they were the major type of inclusion detected in ALS patients homozygous for the wild type-like D90A mutation. The findings suggest that SOD1 may be involved in ALS pathogenesis in patients lacking mutations in the enzyme.

  • 47. Freischmidt, Axel
    et al.
    Mueller, Kathrin
    Zondler, Lisa
    Weydt, Patrick
    Volk, Alexander E.
    Bozic, Anze Losdorfer
    Walter, Michael
    Bonin, Michael
    Mayer, Benjamin
    von Arnim, Christine A. F.
    Otto, Markus
    Dieterich, Christoph
    Holzmann, Karlheinz
    Andersen, Peter
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience. Department of Neurology, Ulm University, Ulm, Germany;Virtual Helmholtz Institute RNA dysmetabolism in Amyotrophic Lateral Sclerosis and Fronto-temporal Dementia, Germany .
    Ludolph, Albert C.
    Danzer, Karin M.
    Weishaupt, Jochen H.
    Serum microRNAs in patients with genetic amyotrophic lateral sclerosis and pre-manifest mutation carriers2014In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 137, no 11, p. 2938-2950Article in journal (Refereed)
    Abstract [en]

    Knowledge about the nature of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis is largely lacking. It could not only pave the way for the discovery of valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained comprehensive expression profiles of microRNAs in the serum of patients with familial amyotrophic lateral sclerosis, asymptomatic mutation carriers and healthy control subjects. We observed a strikingly homogenous microRNA profile in patients with familial amyotrophic lateral sclerosis that was largely independent from the underlying disease gene. Moreover, we identified 24 significantly downregulated microRNAs in pre-manifest amyotrophic lateral sclerosis mutation carriers up to two decades or more before the estimated time window of disease onset; 91.7% of the downregulated microRNAs in mutation carriers overlapped with the patients with familial amyotrophic lateral sclerosis. Bioinformatic analysis revealed a consensus sequence motif present in the vast majority of downregulated microRNAs identified in this study. Our data thus suggest specific common denominators regarding molecular pathogenesis of different amyotrophic lateral sclerosis genes. We describe the earliest pathomolecular alterations in amyotrophic lateral sclerosis mutation carriers known to date, which provide a basis for the discovery of novel therapeutic targets and strongly argue for studies evaluating presymptomatic disease-modifying treatment in amyotrophic lateral sclerosis.

  • 48. Freischmidt, Axel
    et al.
    Wieland, Thomas
    Richter, Benjamin
    Ruf, Wolfgang
    Schaeffer, Veronique
    Mueller, Kathrin
    Marroquin, Nicolai
    Nordin, Frida
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Huebers, Annemarie
    Weydt, Patrick
    Pinto, Susana
    Press, Rayomond
    Millecamps, Stephanie
    Molko, Nicolas
    Bernard, Emilien
    Desnuelle, Claude
    Soriani, Marie-Helene
    Dorst, Johannes
    Graf, Elisabeth
    Nordström, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Feiler, Marisa S.
    Putz, Stefan
    Boeckers, Tobias M.
    Meyer, Thomas
    Winkler, Andrea S.
    Winkelman, Juliane
    de Carvalho, Mamede
    Thal, Dietmar R.
    Otto, Markus
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Volk, Alexander E.
    Kursula, Petri
    Danzer, Karin M.
    Lichtner, Peter
    Dikic, Ivan
    Meitinger, Thomas
    Ludolph, Albert C.
    Strom, Tim M.
    Andersen, Peter M.
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Weishaupt, Jochen H.
    Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia2015In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 18, no 5, p. 631-+Article in journal (Refereed)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

  • 49. Gallo, Valentina
    et al.
    Bueno-De-Mesquita, H Bas
    Vermeulen, Roel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Neurology.
    Kyrozis, Andreas
    Linseisen, Jakob
    Kaaks, Rudolph
    Allen, Naomi E
    Roddam, Andrew W
    Boshuizen, Hendriek C
    Peeters, Petra H
    Palli, Domenico
    Mattiello, Amalia
    Sieri, Sabina
    Tumino, Rosario
    Jiménez-Martín, Juan-Manuel
    Díaz, María José Tormo
    Suarez, Laudina Rodriguez
    Trichopoulou, Antonia
    Agudo, Antonio
    Arriola, Larraitz
    Barricante-Gurrea, Aurelio
    Bingham, Sheila
    Khaw, Kay-Tee
    Manjer, Jonas
    Lindkvist, Björn
    Overvad, Kim
    Bach, Flemming W
    Tjønneland, Anne
    Olsen, Anja
    Bergmann, Manuela M
    Boeing, Heiner
    Clavel-Chapelon, Francoise
    Lund, Eiliv
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Middleton, Lefkos
    Vineis, Paolo
    Riboli, Elio
    Smoking and risk for amyotrophic lateral sclerosis: analysis of the EPIC cohort2009In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 65, no 4, p. 378-385Article in journal (Refereed)
    Abstract [en]

    Objective: Cigarette smoking has been reported as "probable" risk factor for Amyotrophic Lateral Sclerosis (ALS), a poorly understood disease in terms of aetiology. The extensive longitudinal data of the European Prospective Investigation into Cancer and Nutrition (EPIC) were used to evaluate age-specific mortality rates from ALS and the role of cigarette smoking on the risk of dying from ALS.

    Methods: A total of 517,890 healthy subjects were included, resulting in 4,591,325 person-years. ALS cases were ascertained through death certificates. Cox hazard models were built to investigate the role of smoking on the risk of ALS, using packs/years and smoking duration to study dose-response.

    Results: A total of 118 subjects died from ALS, resulting in a crude mortality rate of 2.69 per 100,000/year. Current smokers at recruitment had an almost two-fold increased risk of dying from ALS compared to never smokers (HR = 1.89, 95% C.I. 1.14-3.14), while former smokers at the time of enrollment had a 50% increased risk (HR = 1.48, 95% C.I. 0.94-2.32). The number of years spent smoking increased the risk of ALS (p for trend = 0.002). Those who smoked more than 33 years had more than a two-fold increased risk of ALS compared with never smokers (HR = 2.16, 95% C.I. 1.33-3.53). Conversely, the number of years since quitting smoking was associated with a decreased risk of ALS compared with continuing smoking.

    Interpretation: These results strongly support the hypothesis of a role of cigarette smoking in aetiology of ALS. We hypothesize that this could occur through lipid peroxidation via formaldehyde exposure.

  • 50. Gallo, Valentina
    et al.
    Wark, Petra A.
    Jenab, Mazda
    Pearce, Neil
    Brayne, Carol
    Vermeulen, Roel
    Andersen, Peter M
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Hallmans, Goran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Kyrozis, Andreas
    Vanacore, Nicola
    Vahdaninia, Mariam
    Grote, Verena
    Kaaks, Rudolf
    Mattiello, Amalia
    Bueno-de-Mesquita, H. Bas
    Peeters, Petra H.
    Travis, Ruth C.
    Petersson, Jesper
    Hansson, Oskar
    Arriola, Larraitz
    Jimenez-Martin, Juan-Manuel
    Tjonneland, Anne
    Halkjaer, Jytte
    Agnoli, Claudia
    Sacerdote, Carlotta
    Bonet, Catalina
    Trichopoulou, Antonia
    Gavrila, Diana
    Overvad, Kim
    Weiderpass, Elisabete
    Palli, Domenico
    Ramon Quiros, J.
    Tumino, Rosario
    Khaw, Kay-Tee
    Wareham, Nicholas
    Barricante-Gurrea, Aurelio
    Fedirko, Veronika
    Ferrari, Pietro
    Clavel-Chapelon, Francoise
    Boutron-Ruault, Marie-Christine
    Boeing, Heiner
    Vigl, Matthaeus
    Middleton, Lefkos
    Riboli, Elio
    Vineis, Paolo
    Prediagnostic body fat and risk of death from amyotrophic lateral sclerosis The EPIC cohort2013In: Neurology, ISSN 0028-3878, E-ISSN 1526-632X, Vol. 80, no 9, p. 829-838Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to investigate for the first time the association between body fat and risk of amyotrophic lateral sclerosis (ALS) with an appropriate prospective study design. Methods: The EPIC (European Prospective Investigation into Cancer and Nutrition) study included 518,108 individuals recruited from the general population across 10 Western European countries. At recruitment, information on lifestyle was collected and anthropometric characteristics were measured. Cox hazard models were fitted to investigate the associations between anthropometric measures and ALS mortality. Results: Two hundred twenty-two ALS deaths (79 men and 143 women) occurred during the follow-up period (mean follow-up = 13 years). There was a statistically significant interaction between categories of body mass index and sex regarding ALS risk (p = 0.009): in men, a significant linear decrease of risk per unit of body mass index was observed (hazard ratio = 0.93, 95% confidence interval 0.86-0.99 per kg/m(2)); among women, the risk was more than 3-fold increased for underweight compared with normal-weight women. Among women, a significant risk reduction increasing the waist/hip ratio was also evident: women in the top quartile had less than half the risk of ALS compared with those in the bottom quartile (hazard ratio = 0.48, 95% confidence interval 0.25-0.93) with a borderline significant p value for trend across quartiles (p = 0.056). Conclusion: Increased prediagnostic body fat is associated with a decreased risk of ALS mortality. Neurology (R) 2013; 80: 829-838

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