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BETA
Andersen, Peter M.
Alternative names
Publications (10 of 175) Show all publications
Miltenberger-Miltenyi, G., Conceicao, V. A., Gromicho, M., Pronto-Laborinho, A. C., Pinto, S., Andersen, P. M. & de Carvalho, M. (2019). C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis [Letter to the editor]. Journal of Neurology, Neurosurgery and Psychiatry, 90(1), 118-120
Open this publication in new window or tab >>C9orf72 expansion is associated with accelerated decline of respiratory function and decreased survival in amyotrophic lateral sclerosis
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 1, p. 118-120Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-157235 (URN)10.1136/jnnp-2018-318032 (DOI)000459181800022 ()29661924 (PubMedID)
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-03-20Bibliographically approved
Oeckl, P., Weydt, P., Steinacker, P., Anderl-Straub, S., Nordin, F., Volk, A. E., . . . Otto, M. (2019). Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase. Journal of Neurology, Neurosurgery and Psychiatry, 90(1), 4-10
Open this publication in new window or tab >>Different neuroinflammatory profile in amyotrophic lateral sclerosis and frontotemporal dementia is linked to the clinical phase
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 1, p. 4-10Article in journal (Refereed) Published
Abstract [en]

Objective: To investigate the role of neuroinflammation in asymptomatic and symptomatic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mutation carriers.

Methods: The neuroinflammatory markers chitotriosidase 1 (CHIT1), YKL-40 and glial fibrillary acidic protein (GFAP) were measured in cerebrospinal fluid (CSF) and blood samples from asymptomatic and symptomatic ALS/FTD mutation carriers, sporadic cases and controls by ELISA.

Results: CSF levels of CHIT1, YKL-40 and GFAP were unaffected in asymptomatic mutation carriers (n=16). CHIT1 and YKL-40 were increased in gALS (p<0.001, n=65) whereas GFAP was not affected. Patients with ALS carrying a CHIT1 polymorphism had lower CHIT1 concentrations in CSF (-80%) whereas this polymorphism had no influence on disease severity. In gFTD (n=23), increased YKL-40 and GFAP were observed (p<0.05), whereas CHIT1 was nearly not affected. The same profile as in gALS and gFTD was observed in sALS (n=64/70) and sFTD (n=20/26). CSF and blood concentrations correlated moderately (CHIT1, r=0.51) to weak (YKL-40, r=0.30, GFAP, r=0.39). Blood concentrations of these three markers were not significantly altered in any of the groups except CHIT1 in gALS of the Ulm cohort (p<0.05).

Conclusion: Our data indicate that neuroinflammation is linked to the symptomatic phase of ALS/FTD and shows a similar pattern in sporadic and genetic cases. ALS and FTD are characterised by a different neuroinflammatory profile, which might be one driver of the diverse presentations of the ALS/FTD syndrome.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-157233 (URN)10.1136/jnnp-2018-318868 (DOI)000459181800004 ()30224549 (PubMedID)
Available from: 2019-03-20 Created: 2019-03-20 Last updated: 2019-03-20Bibliographically approved
Brännström, T., Andersen, P. M., Bergh, J., Ekhtiari Bidhendi, E. & Marklund, S. M. (2019). Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease. Paper presented at 19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN. Brain Pathology, 29, 90-90
Open this publication in new window or tab >>Mutant SOD1 aggregates from human ventral horn transmit templated aggregation and fatal ALS-like disease
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2019 (English)In: Brain Pathology, ISSN 1015-6305, E-ISSN 1750-3639, Vol. 29, p. 90-90Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
John Wiley & Sons, 2019
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-157592 (URN)000459814800279 ()
Conference
19th International Congress of Neuropathology, SEP 23-27, 2018, Tokyo, JAPAN
Note

Supplement: 1

Special Issue: SI

Meeting Abstract: P2-66

Available from: 2019-03-28 Created: 2019-03-28 Last updated: 2019-03-28Bibliographically approved
Keskin, I., Forsgren, E., Lehmann, M., Andersen, P. M., Brännström, T., Lange, D. J., . . . Gilthorpe, J. D. (2019). The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension. Acta Neuropathologica
Open this publication in new window or tab >>The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
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2019 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533Article in journal (Refereed) Epub ahead of print
Abstract [en]

Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O2 is required for formation of the bond, we reasoned that low O2 tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low oxygen tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O2 tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.

Place, publisher, year, edition, pages
New York: Springer, 2019
Keywords
Amyotrophic lateral sclerosis (ALS), Superoxide dismutase 1 (SOD1), Disulfide bond, Oxygen tension, Protein disorder, Protein aggregation, Patient-derived cells
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-157037 (URN)10.1007/s00401-019-01986-1 (DOI)
Note

Originally included in thesis in manuscript form.

Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-04-01
Canosa, A., De Marco, G., Lomartire, A., Rinaudo, M. T., Di Cunto, F., Turco, E., . . . Chio, A. (2018). A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms. Neurobiology of Aging, 72
Open this publication in new window or tab >>A novel p.Ser108LeufsTer15 SOD1 mutation leading to the formation of a premature stop codon in an apparently sporadic ALS patient: insights into the underlying pathomechanisms
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2018 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 72Article in journal (Refereed) Published
Abstract [en]

We report an apparently sporadic amyotrophic lateral sclerosis patient carrying a heterozygous novel frameshift SOD1 mutation (p.Ser108LeufsTer15), predicted to cause a premature protein truncation. RTPCR analysis of SOD1 mRNA and SDS-PAGE/Western blot analysis of PBMC demonstrated that mRNA from the mutant allele is expressed at levels similar to those of the wild-type allele, but the truncated protein is undetectable also in the insoluble fraction and after proteasome inhibition. Accordingly, the dismutation activity in erythrocytes is halved. Thus, the pathogenic mechanism associated with this mutation might be based on an insufficient activity of SOD1 that would make motor neurons more vulnerable to oxidative injury. However, it cannot be excluded that p.Ser108LeufsTer15 SOD1 is present in the nervous tissue and, being less charged and hence having less repulsive forces than the wild-type protein, may trigger toxic mechanisms as a consequence of its propensity to aggregate. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Amyotrophic lateral sclerosis, SOD1, Truncated protein, Frameshift mutation, Oxidative stress, Protein aggregation
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-153540 (URN)10.1016/j.neurobiolaging.2018.08.014 (DOI)000449073700028 ()30236613 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Brockmann, S. J., Freischmidt, A., Oeckl, P., Müller, K., Ponna, S. K., Helferich, A. M., . . . Weishaupt, J. H. (2018). CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency. Human Molecular Genetics, 27(4), 706-715
Open this publication in new window or tab >>CHCHD10 mutations p.R15L and p.G66V cause motoneuron disease by haploinsufficiency
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2018 (English)In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 27, no 4, p. 706-715Article in journal (Refereed) Published
Abstract [en]

Mutations in the mitochondrially located protein CHCHD10 cause motoneuron disease by an unknown mechanism. In this study, we investigate the mutations p. R15L and p. G66V in comparison to wild-type CHCHD10 and the non-pathogenic variant p. P34S in vitro, in patient cells as well as in the vertebrate in vivo model zebrafish. We demonstrate a reduction of CHCHD10 protein levels in p. R15L and p. G66V mutant patient cells to approximately 50%. Quantitative real-time PCR revealed that expression of CHCHD10 p. R15L, but not of CHCHD10 p. G66V, is already abrogated at the mRNA level. Altered secondary structure and rapid protein degradation are observed with regard to the CHCHD10 p. G66V mutant. In contrast, no significant differences in expression, degradation rate or secondary structure of non-pathogenic CHCHD10 p. P34S are detected when compared with wild-type protein. Knockdown of CHCHD10 expression in zebrafish to about 50% causes motoneuron pathology, abnormal myofibrillar structure and motility deficits in vivo. Thus, our data show that the CHCHD10 mutations p. R15L and p. G66V cause motoneuron disease primarily based on haploinsufficiency of CHCHD10.

Place, publisher, year, edition, pages
Oxford University Press, 2018
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-145134 (URN)10.1093/hmg/ddx436 (DOI)000424137500011 ()29315381 (PubMedID)
Available from: 2018-03-05 Created: 2018-03-05 Last updated: 2018-06-09Bibliographically approved
Mueller, K., Brenner, D., Weydt, P., Meyer, T., Grehl, T., Petri, S., . . . Weishaupt, J. H. (2018). Comprehensive analysis of the mutation spectrum in 301 German ALS families. Journal of Neurology, Neurosurgery and Psychiatry, 89(8), 817-827
Open this publication in new window or tab >>Comprehensive analysis of the mutation spectrum in 301 German ALS families
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2018 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 89, no 8, p. 817-827Article in journal (Refereed) Published
Abstract [en]

Objectives Recent advances in amyotrophic lateral sclerosis (ALS) genetics have revealed that mutations in any of more than 25 genes can cause ALS, mostly as an autosomal-dominant Mendelian trait. Detailed knowledge about the genetic architecture of ALS in a specific population will be important for genetic counselling but also for genotype-specific therapeutic interventions.

Methods Here we combined fragment length analysis, repeat-primed PCR, Southern blotting, Sanger sequencing and whole exome sequencing to obtain a comprehensive profile of genetic variants in ALS disease genes in 301 German pedigrees with familial ALS. We report C9orf72 mutations as well as variants in consensus splice sites and non-synonymous variants in protein-coding regions of ALS genes. We furthermore estimate their pathogenicity by taking into account type and frequency of the respective variant as well as segregation within the families.

Results 49% of our German ALS families carried a likely pathogenic variant in at least one of the earlier identified ALS genes. In 45% of the ALS families, likely pathogenic variants were detected in C9orf72, SOD1, FUS, TARDBP or TBK1, whereas the relative contribution of the other ALS genes in this familial ALS cohort was 4%. We identified several previously unreported rare variants and demonstrated the absence of likely pathogenic variants in some of the recently described ALS disease genes.

Conclusions We here present a comprehensive genetic characterisation of German familial ALS. The present findings are of importance for genetic counselling in clinical practice, for molecular research and for the design of diagnostic gene panels or genotype-specific therapeutic interventions in Europe.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2018
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-151563 (URN)10.1136/jnnp-2017-317611 (DOI)000442475000013 ()29650794 (PubMedID)
Available from: 2018-09-10 Created: 2018-09-10 Last updated: 2018-09-10Bibliographically approved
Volk, A. E., Weishaupt, J. H., Andersen, P. M., Ludolph, A. C. & Kubisch, C. (2018). Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis. Medizinische Genetik, 30(2), 252-258
Open this publication in new window or tab >>Current knowledge and recent insights into the genetic basis of amyotrophic lateral sclerosis
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2018 (English)In: Medizinische Genetik, ISSN 1863-5490, Vol. 30, no 2, p. 252-258Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease, affecting the upper and/or lower motor neurons. However, extramotor symptoms can also occur; cognitive deficits are present in more than 40% of patients and 5-8% of ALS patients develop frontotemporal dementia. There is no effective treatment for ALS and median survival is 2-3 years after onset.

Amyotrophic lateral sclerosis is a genetically heterogeneous disorder with monogenic forms as well as complex genetic etiology. Currently, complex genetic risk factors are of minor interest for routine diagnostic testing or counseling of patients and their families. By contrast, a monogenic cause can be identified in 70% of familial and 10% of sporadic ALS cases. The most frequent genetic cause is a noncoding hexanucleotide repeat expansion in the C9orf72 gene. In recent years, high-throughput sequencing technologies have helped to identify additional monogenic and complex risk factors of ALS.

Genetic counseling should be offered to all ALS patients and their first- and possibly second-degree relatives, and should include information about the possibilities and limitations of genetic testing. Routine diagnostic testing should at least encompass the most frequently mutated disease genes (C9orf72, SOD1, TDP-43, FUS). Targeted sequencing approaches including further disease genes may be applied. Caution is warranted as the C9orf72 repeat expansion cannot be detected by routine sequencing technologies and testing by polymerase chain reaction (PCR) is failure-prone.

Predictive testing is possible in families in which a genetic cause has been identified, but the limitations of genetic testing (i.aEuro<overline>e., the problems of incomplete penetrance, variable expressivity and possible oligogenic inheritance) have to be explained to the families.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2018
Keywords
Motor neuron disease, Genetic heterogeneity, C9orf72, Oligogenic inheritance, Predictive testing
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-152232 (URN)10.1007/s11825-018-0185-3 (DOI)000443457600005 ()30220791 (PubMedID)
Available from: 2018-10-25 Created: 2018-10-25 Last updated: 2018-10-25Bibliographically approved
Helferich, A. M., Brockmann, S. J., Reinders, J., Deshpande, D., Holzmann, K., Brenner, D., . . . Weishaupt, J. H. (2018). Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS. Cellular and Molecular Life Sciences (CMLS), 75(23), 4301-4319
Open this publication in new window or tab >>Dysregulation of a novel miR-1825/TBCB/TUBA4A pathway in sporadic and familial ALS
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2018 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 75, no 23, p. 4301-4319Article in journal (Refereed) Published
Abstract [en]

Genetic and functional studies suggest diverse pathways being affected in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), while knowledge about converging disease mechanisms is rare. We detected a downregulation of microRNA-1825 in CNS and extra-CNS system organs of both sporadic (sALS) and familial ALS (fALS) patients. Combined transcriptomic and proteomic analysis revealed that reduced levels of microRNA-1825 caused a translational upregulation of tubulin-folding cofactor b (TBCB). Moreover, we found that excess TBCB led to depolymerization and degradation of tubulin alpha-4A (TUBA4A), which is encoded by a known ALS gene. Importantly, the increase in TBCB and reduction of TUBA4A protein was confirmed in brain cortex tissue of fALS and sALS patients, and led to motor axon defects in an in vivo model. Our discovery of a microRNA-1825/TBCB/TUBA4A pathway reveals a putative pathogenic cascade in both fALS and sALS extending the relevance of TUBA4A to a large proportion of ALS cases.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Amyotrophic lateral sclerosis, Frontotemporal dementia, MicroRNA, TBCE, Microtubules, Zebrafish
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-153539 (URN)10.1007/s00018-018-2873-1 (DOI)000449307300003 ()30030593 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2018-11-26Bibliographically approved
Gromicho, M., Pinto, S., Gisca, E., Pronto-Laborinho, A. C., Andersen, P. M. & de Carvalho, M. (2018). Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis. Neurobiology of Aging, 70, Article ID 325.e7.
Open this publication in new window or tab >>Frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese patients with amyotrophic lateral sclerosis
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2018 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 70, article id 325.e7Article in journal (Refereed) Published
Abstract [en]

Mutation frequency of the 2 main amyotrophic lateral sclerosis (ALS) erelated genes, C9orf72 and SOD1, varies considerably across the world. We analyzed those genes in a large population of Portuguese ALS patients (n = 371) and recorded demographic and clinical features. Familial ALS (FALS) was disclosed in 11.6% of patients. Mutations in either SOD1 or C9orf72 were found in 9.2% of patients and accounted for 40% of FALS and 5.2% of sporadic ALS. SOD1 mutations were rare (0.83%), but a novel and probably disease-causing mutation was identified: p. Ala152Pro (c. 457G>C). The C9orf72 hexanucleotide repeat expansion was the commonest abnormality, accounting for 4.6% of sporadic ALS and 37.5% of FALS; in these patients, Frontotemporal Dementia was prevalent. This first report on the frequency of C9orf72 hexanucleotide repeat expansion and SOD1 mutations in Portuguese ALS patients reiterate that the genetic architecture of ALS varies among different geographic regions. The mutations incidence in ALS patients (w10%) and associated phenotypes suggest that genetic tests should be offered to more patients, and other genes should be investigated in our population. 

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
Amyotrophic lateral sclerosis, C9orf72 hexanucleotide repeat expansion, SOD1, Mutation, Phenotype, Frontotemporal dementia
National Category
Neurology
Identifiers
urn:nbn:se:umu:diva-151518 (URN)10.1016/j.neurobiolaging.2018.05.009 (DOI)000442879100034 ()29861044 (PubMedID)
Funder
Swedish Research Council
Available from: 2018-09-13 Created: 2018-09-13 Last updated: 2018-09-13Bibliographically approved
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