umu.sePublications
Change search
Link to record
Permanent link

Direct link
BETA
Andersen, Peter M.
Alternative names
Publications (10 of 169) Show all publications
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
Show others...
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
Show others...
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
Show others...
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
Show others...
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
Show others...
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
Show others...
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
Nicolas, A., Kenna, K. P., Renton, A. E., Ticozzi, N., Faghri, F., Chia, R., . . . Landers, J. E. (2018). Genome-wide Analyses Identify KIF5A as a Novel ALS Gene. Neuron, 97(6), 1268-1283.e6
Open this publication in new window or tab >>Genome-wide Analyses Identify KIF5A as a Novel ALS Gene
Show others...
2018 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 97, no 6, p. 1268-1283.e6Article in journal (Refereed) Published
Abstract [en]

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.

Place, publisher, year, edition, pages
Cell Press, 2018
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-146567 (URN)10.1016/j.neuron.2018.02.027 (DOI)000428235400013 ()29566793 (PubMedID)
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-06-09Bibliographically approved
Brenner, D., Yilmaz, R., Müller, K., Grehl, T., Petri, S., Meyer, T., . . . Weishaupt, J. H. (2018). Hot-spot KIF5A mutations cause familial ALS. Brain, 141, 688-697
Open this publication in new window or tab >>Hot-spot KIF5A mutations cause familial ALS
Show others...
2018 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, p. 688-697Article in journal (Refereed) Published
Abstract [en]

Heterozygous missense mutations in the N-terminal motor or coiled-coil domains of the kinesin family member 5A (KIF5A) gene cause monogenic spastic paraplegia (HSP10) and Charcot-Marie-Tooth disease type 2 (CMT2). Moreover, heterozygous de novo frame-shift mutations in the C-terminal domain of KIF5A are associated with neonatal intractable myoclonus, a neurodevelopmental syndrome. These findings, together with the observation that many of the disease genes associated with amyotrophic lateral sclerosis disrupt cytoskeletal function and intracellular transport, led us to hypothesize that mutations in KIF5A are also a cause of amyotrophic lateral sclerosis. Using whole exome sequencing followed by rare variant analysis of 426 patients with familial amyotrophic lateral sclerosis and 6137 control subjects, we detected an enrichment of KIF5A splice-site mutations in amyotrophic lateral sclerosis (2/426 compared to 0/6137 in controls; P = 4.2 x 10-3), both located in a hot-spot in the C-terminus of the protein and predicted to affect splicing exon 27. We additionally show co-segregation with amyotrophic lateral sclerosis of two canonical splice-site mutations in two families. Investigation of lymphoblast cell lines from patients with KIF5A splice-site mutations revealed the loss of mutant RNA expression and suggested haploinsufficiency as the most probable underlying molecular mechanism. Furthermore, mRNA sequencing of a rare non-synonymous missense mutation (predicting p. Arg1007Gly) located in the C-terminus of the protein shortly upstream of the splice donor of exon 27 revealed defective KIF5A pre-mRNA splicing in respective patient-derived cell lines owing to abrogation of the donor site. Finally, the non-synonymous single nucleotide variant rs113247976 (minor allele frequency = 1.00% in controls, n = 6137), also located in the C-terminal region [p.(Pro986Leu) in exon 26], was significantly enriched in familial amyotrophic lateral sclerosis patients (minor allele frequency = 3.40%; P = 1.28 x 10-7). Our study demonstrates that mutations located specifically in a C-terminal hotspot of KIF5A can cause a classical amyotrophic lateral sclerosis phenotype, and underline the involvement of intracellular transport processes in amyotrophic lateral sclerosis pathogenesis.

Place, publisher, year, edition, pages
Oxford University Press, 2018
Keywords
ALS, KIF5A mutations, axonal transport, whole exome sequencing
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-146237 (URN)10.1093/brain/awx370 (DOI)000426813600016 ()29342275 (PubMedID)
Available from: 2018-04-09 Created: 2018-04-09 Last updated: 2018-06-09Bibliographically approved
Ekhtiari Bidhendi, E., Bergh, J., Zetterström, P., Forsberg, K., Pakkenberg, B., Andersen, P. M., . . . Brännström, T. (2018). Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis. Acta Neuropathologica, 136(6), 939-953
Open this publication in new window or tab >>Mutant superoxide dismutase aggregates from human spinal cord transmit amyotrophic lateral sclerosis
Show others...
2018 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Other academic) Published
Abstract [en]

Motor neurons containing aggregates of superoxide dismutase 1 (SOD1) are hallmarks of amyotrophic lateral sclerosis (ALS) caused by mutations in the gene encoding SOD1. We have previously reported that two strains of mutant human (h) SOD1 aggregates (denoted A and B) can arise in hSOD1-transgenic models for ALS and that inoculation of such aggregates into the lumbar spinal cord of mice results in rostrally spreading, templated hSOD1 aggregation and premature fatal ALS-like disease. Here, we explored whether mutant hSOD1 aggregates with prion-like properties also exist in human ALS. Aggregate seeds were prepared from spinal cords from an ALS patient carrying the hSOD1G127Gfs*7 truncation mutation and from mice transgenic for the same mutation. To separate from mono-, di- or any oligomeric hSOD1 species, the seed preparation protocol included ultracentrifugation through a density cushion. The core structure of hSOD1G127Gfs*7 aggregates present in mice was strain A-like. Inoculation of the patient- or mouse-derived seeds into lumbar spinal cord of adult hSOD1-expressing mice induced strain A aggregation propagating along the neuraxis and premature fatal ALS-like disease (p < 0.0001). Inoculation of human or murine control seeds had no effect. The potencies of the ALS patient-derived seed preparations were high and disease was initiated in the transgenic mice by levels of hSOD1G127Gfs*7 aggregates much lower than those found in the motor system of patients carrying the mutation. The results suggest that prion-like growth and spread of hSOD1 aggregation could be the primary pathogenic mechanism, not only in hSOD1 transgenic rodent models, but also in human ALS.

Place, publisher, year, edition, pages
Springer, 2018
Keywords
Superoxide dismutase, prion-like, aggregation, propagation, motor neuron disease
National Category
Neurosciences
Research subject
Neurology; Pathology
Identifiers
urn:nbn:se:umu:diva-150909 (URN)10.1007/s00401-018-1915-y (DOI)000451952700008 ()30284034 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationTorsten Söderbergs stiftelseThe Swedish Brain FoundationThe Kempe FoundationsVästerbotten County Council
Note

Originally included in thesis in manuscript form.

Available from: 2018-08-18 Created: 2018-08-18 Last updated: 2019-01-04Bibliographically approved
Higelin, J., Catanese, A., Semelink-Sedlacek, L. L., Oeztuerk, S., Lutz, A.-K., Bausinger, J., . . . Boeckers, T. M. (2018). NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons. Stem Cell Research, 30, 150-162
Open this publication in new window or tab >>NEK1 loss-of-function mutation induces DNA damage accumulation in ALS patient-derived motoneurons
Show others...
2018 (English)In: Stem Cell Research, ISSN 1873-5061, E-ISSN 1876-7753, Vol. 30, p. 150-162Article in journal (Refereed) Published
Abstract [en]

Mutations in genes coding for proteins involved in DNA damage response (DDR) and repair, such as C9orf72 and FUS (Fused in Sarcoma), are associated with neurodegenerative diseases and lead to amyotrophic lateral sclerosis (ALS). Heterozygous loss-of-function mutations in NEK1 (NIMA-related kinase 1) have also been recently found to cause ALS. NEK1 codes for a multifunctional protein, crucially involved in mitotic checkpoint control and DDR. To resolve pathological alterations associated with NEK1 mutation, we compared hiPSC-derived motoneurons carrying a NEK1 mutation with mutant C9orf72 and wild type neurons at basal level and after DNA damage induction. Motoneurons carrying a C9orf72 mutation exhibited cell specific signs of increased DNA damage. This phenotype was even more severe in NEK1c.2434A>T neurons that showed significantly increased DNA damage at basal level and impaired DDR after induction of DNA damage in an maturation-dependent manner. Our results provide first mechanistic insight in pathophysiological alterations induced by NEK1 mutations and point to a converging pathomechanism of different gene mutations causative for ALS. Therefore, our study contributes to the development of novel therapeutic strategies to reduce DNA damage accumulation in neurodegenerative diseases and ALS.

Place, publisher, year, edition, pages
Elsevier, 2018
Keywords
hiPSC, ALS, NEK1, neurodegeneration, DNA damage
National Category
Medical Genetics Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-150372 (URN)10.1016/j.scr.2018.06.005 (DOI)000438786600020 ()29929116 (PubMedID)2-s2.0-85048705749 (Scopus ID)
Available from: 2018-08-08 Created: 2018-08-08 Last updated: 2018-08-08Bibliographically approved
Organisations

Search in DiVA

Show all publications