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Forsberg, K., Graffmo, K. S., Pakkenberg, B., Weber, M., Nielsen, M., Marklund, S. L., . . . Munch Andersen, P. (2019). Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes. Journal of Neurology, Neurosurgery and Psychiatry, 90(8), 861-869
Open this publication in new window or tab >>Misfolded SOD1 inclusions in patients with mutations in C9orf72 and other ALS/FTD-associated genes
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2019 (English)In: Journal of Neurology, Neurosurgery and Psychiatry, ISSN 0022-3050, E-ISSN 1468-330X, Vol. 90, no 8, p. 861-869Article in journal (Refereed) Published
Abstract [en]

Objective: A hallmark of amyotrophic lateral sclerosis (ALS) caused by mutations in superoxide dismutase-1 (SOD1) are inclusions containing SOD1 in motor neurons. Here, we searched for SOD1-positive inclusions in 29 patients carrying ALS-linked mutations in six other genes.

Methods: A panel of antibodies that specifically recognise misfolded SOD1 species were used for immunohistochemical investigations of autopsy tissue.

Results: The 18 patients with hexanucleotide-repeat-expansions in C9orf72 had inclusions of misfolded wild type (WT) SOD1(WT) in spinal motor neurons. Similar inclusions were occasionally observed in medulla oblongata and in the motor cortex and frontal lobe. Patients with mutations in FUS, KIF5A, NEK1, ALSIN or VAPB, carried similar SOD1(WT) inclusions. Minute amounts of misSOD1(WT) inclusions were detected in 2 of 20 patients deceased from non-neurological causes and in 4 of 10 patients with other neurodegenerative diseases. Comparison was made with 17 patients with 9 different SOD1 mutations. Morphologically, the inclusions in patients with mutations in C9orf72HRE, FUS, KIF5A, NEK1, VAPB and ALSIN resembled inclusions in patients carrying the wildtype-like SOD1(D90A) mutation, whereas patients carrying unstable SOD1 mutations (A4V, V5M, D76Y, D83G, D101G, G114A, G127X, L144F) had larger skein-like SOD1-positive inclusions.

Conclusions and relevance Abundant inclusions containing misfolded SOD1(WT) are found in spinal and cortical motor neurons in patients carrying mutations in six ALS-causing genes other than SOD1. This suggests that misfolding of SOD1(WT) can be part of a common downstream event that may be pathogenic. The new anti-SOD1 therapeutics in development may have applications for a broader range of patients.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2019
Keywords
amyotrophic lateral sclerosis, neuronal inclusions, C9orf72, KIF5A, superoxide dismutase-1
National Category
Neurology Neurosciences
Identifiers
urn:nbn:se:umu:diva-163689 (URN)10.1136/jnnp-2018-319386 (DOI)000482509400004 ()30992335 (PubMedID)
Available from: 2019-10-17 Created: 2019-10-17 Last updated: 2019-10-17Bibliographically 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
Andersen, P. M., Hempel, M., Santer, R., Nordström, U., Tsiakas, K., Johannsen, J., . . . Marklund, S. L. (2019). Phenotype in an Infant with SOD1 Homozygous Truncating Mutation [Letter to the editor]. New England Journal of Medicine, 381(5), 486-488
Open this publication in new window or tab >>Phenotype in an Infant with SOD1 Homozygous Truncating Mutation
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2019 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 5, p. 486-488Article in journal, Letter (Refereed) Published
Place, publisher, year, edition, pages
Massachusetts Medical Society, 2019
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-162395 (URN)10.1056/NEJMc1905039 (DOI)000478064200016 ()31314961 (PubMedID)
Available from: 2019-08-20 Created: 2019-08-20 Last updated: 2019-08-20Bibliographically approved
Tokuda, E., Marklund, S. L. & Furukawa, Y. (2019). Prion-like Properties of Misfolded Cu/Zn-superoxide Dismutase in Amyotrophic Lateral Sclerosis: Update and Perspectives. Yakugaku zasshi, 139(7), 1015-1019
Open this publication in new window or tab >>Prion-like Properties of Misfolded Cu/Zn-superoxide Dismutase in Amyotrophic Lateral Sclerosis: Update and Perspectives
2019 (English)In: Yakugaku zasshi, ISSN 0031-6903, E-ISSN 1347-5231, Vol. 139, no 7, p. 1015-1019Article, review/survey (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease that is characterized by the loss of motor neurons, which results in progressive muscle atrophy. The pathology spreads from the initial site of onset to contiguous anatomic regions. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD1) have been identified in a dominantly inherited form of ALS (ALS-SOD1). A major hallmark of ALS-SOD1 is the abnormal accumulation of conformationally aberrant SOD1 protein (i.e., misfolded SOD1) within motor neurons. Emerging experimental evidence has suggested that misfolded proteins associated with neurodegenerative diseases exhibit prion-like properties, i.e., misfolded proteins act as conformational templates that convert normal proteins into a pathogenic form. Possibly as a result of this prion-like self-propagation property, misfolded forms of pathological proteins are considered to accumulate in the central nervous system and cause neurodegeneration. In this article, we review recent evidence for the role of prion-like mechanisms in ALS-SOD1. In particular, we discuss the propensity of misfolded SOD1 to act as a pathological seed, spread between cells, and propagate neuroanatomically.

Place, publisher, year, edition, pages
Pharmaceutical Society of Japan, 2019
Keywords
amyotrophic lateral sclerosis, superoxide dismutase-1, prion-like propagation
National Category
Neurosciences Neurology
Identifiers
urn:nbn:se:umu:diva-161704 (URN)10.1248/yakushi.18-00165-5 (DOI)000473562600009 ()31257248 (PubMedID)
Available from: 2019-08-05 Created: 2019-08-05 Last updated: 2019-09-03Bibliographically 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, 138(1), 85-101
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 1432-0533, Vol. 138, no 1, p. 85-101Article in journal (Refereed) Published
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)000471708700005 ()30863976 (PubMedID)
Funder
Swedish Research Council, VRMH 2015-02804Knut and Alice Wallenberg Foundation, 2012.0091Västerbotten County CouncilThe Kempe FoundationsThe Swedish Brain Foundation, Hjarnfonden FO2015-0234
Note

Originally included in thesis in manuscript form.

Available from: 2019-03-06 Created: 2019-03-06 Last updated: 2019-07-12Bibliographically approved
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
Paré, B., Lehmann, M., Beaudin, M., Nordström, U., Saikali, S., Julien, J.-P., . . . Gros-Louis, F. (2018). Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis. Scientific Reports, 8, Article ID 14223.
Open this publication in new window or tab >>Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis
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2018 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 14223Article in journal (Refereed) Published
Abstract [en]

Aggregation of mutant superoxide dismutase 1 (SOD1) is a pathological hallmark of a subset of familial ALS patients. However, the possible role of misfolded wild type SOD1 in human ALS is highly debated. To ascertain whether or not misfolded SOD1 is a common pathological feature in non-SOD1 ALS, we performed a blinded histological and biochemical analysis of post mortem brain and spinal cord tissues from 19 sporadic ALS, compared with a SOD1 A4V patient as well as Alzheimer's disease (AD) and non-neurological controls. Multiple conformation-or misfolded-specific antibodies for human SOD1 were compared. These were generated independently by different research groups and were compared using standardized conditions. Five different misSOD1 staining patterns were found consistently in tissue sections from SALS cases and the SOD1 A4V patient, but were essentially absent in AD and non-neurological controls. We have established clear experimental protocols and provide specific guidelines for working, with conformational/misfolded SOD1-specific antibodies. Adherence to these guidelines will aid in the comparison of the results of future studies and better interpretation of staining patterns. This blinded, standardized and unbiased approach provides further support for a possible pathological role of misSOD1 in SALS.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Neurosciences Other Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-152398 (URN)10.1038/s41598-018-31773-z (DOI)000445276500004 ()30242181 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg FoundationRagnar Söderbergs stiftelseTorsten Söderbergs stiftelseThe Swedish Brain FoundationVästerbotten County CouncilThe Kempe Foundations
Available from: 2018-10-05 Created: 2018-10-05 Last updated: 2019-05-20Bibliographically 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
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2018 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 136, no 6, p. 939-953Article in journal (Refereed) 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: 2019-09-12Bibliographically approved
Keskin, I., Birve, A., Berdynski, M., Hjertkvist, K., Rofougaran, R., Nilsson, T. K., . . . Andersen, P. M. (2017). Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 18(5-6), 457-463
Open this publication in new window or tab >>Comprehensive analysis to explain reduced or increased SOD1 enzymatic activity in ALS patients and their relatives
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2017 (English)In: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, ISSN 2167-8421, E-ISSN 2167-9223, Vol. 18, no 5-6, p. 457-463Article in journal (Refereed) Published
Abstract [en]

Objective: To characterise stabilities in erythrocytes of mutant SOD1 proteins, compare SOD1 enzymatic activities between patients with different genetic causes of ALS and search for underlying causes of deviant SOD1 activities in individuals lacking SOD1 mutations.Methods: Blood samples from 4072 individuals, ALS patients with or without a SOD1 mutation, family members and controls were studied. Erythrocyte SOD1 enzymatic activities normalised to haemoglobin content were determined, and effects of haemoglobin disorders on dismutation assessed. Coding SOD1 sequences were analysed by Sanger sequencing, exon copy number variations by fragment length analysis and by TaqMan Assay.Results: Of the 44 SOD1 mutations found, 75% caused severe destabilisation of the mutant protein but in 25% it was physically stable. Mutations producing structural changes caused halved erythrocyte SOD1 activities. There were no differences in SOD1 activities between patients without a SOD1 mutation and control individuals or carriers of TBK1 mutations and C9orf72(HRE). In the low and high SOD1 activity groups no deviations were found in exon copy numbers and intron gross structures. Thalassemias and iron deficiency were associated with increased SOD1 activity/haemoglobin ratios.Conclusion: Adjunct erythrocyte SOD1 activity analysis reliably signals destabilising SOD1 mutations including intronic mutations that are missed by exon sequencing.

Place, publisher, year, edition, pages
TAYLOR & FRANCIS LTD, 2017
Keywords
Amyotrophic lateral sclerosis, superoxide dismutase, mutation, enzymatic activity
National Category
Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-138241 (URN)10.1080/21678421.2017.1301481 (DOI)000405584600019 ()
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2018-06-09Bibliographically approved
Lange, D. J., Shahbazi, M., Silani, V., Ludolph, A. C., Weishaupt, J. H., Ajroud-Driss, S., . . . Andersen, P. M. (2017). Pyrimethamine Significantly Lowers Cerebrospinal Fluid Cu/Zn Superoxide Dismutase in Amyotrophic Lateral Sclerosis Patients with SOD1 Mutations. Annals of Neurology, 81(6), 837-848
Open this publication in new window or tab >>Pyrimethamine Significantly Lowers Cerebrospinal Fluid Cu/Zn Superoxide Dismutase in Amyotrophic Lateral Sclerosis Patients with SOD1 Mutations
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2017 (English)In: Annals of Neurology, ISSN 0364-5134, E-ISSN 1531-8249, Vol. 81, no 6, p. 837-848Article in journal (Refereed) Published
Abstract [en]

Objective: Cu/Zn superoxide dismutase (SOD1) reduction prolongs survival in SOD1-transgenic animal models. Pyrimethamine produces dose-dependent SOD1 reduction in cell culture systems. A previous phase 1 trial showed pyrimethamine lowers SOD1 levels in leukocytes in patients with SOD1 mutations. This study investigated whether pyrimethamine lowered SOD1 levels in the cerebrospinal fluid (CSF) in patients carrying SOD1 mutations linked to familial amyotrophic lateral sclerosis (fALS/SOD1). Methods: A multicenter (5 sites), open-label, 9-month-duration, dose-ranging study was undertaken to determine the safety and efficacy of pyrimethamine to lower SOD1 levels in the CSF in fALS/SOD1. All participants underwent 3 lumbar punctures, blood draw, clinical assessment of strength, motor function, quality of life, and adverse effect assessments. SOD1 levels were measured in erythrocytes and CSF. Pyrimethamine was measured in plasma and CSF. Appel ALS score, ALS Functional Rating Scale-Revised, and McGill Quality of Life Single-Item Scale were measured at screening, visit 6, and visit 9. Results: We enrolled 32 patients; 24 completed 6 visits (18 weeks), and 21 completed all study visits. A linear mixed effects model showed a significant reduction in CSF SOD1 at visit 6 (p<0.001) with a mean reduction of 13.5% (95% confidence interval [CI] 58.4-18.5) and at visit 9 (p<0.001) with a mean reduction of 10.5% (95% CI55.2-15.8). Interpretation: Pyrimethamine is safe and well tolerated in ALS. Pyrimethamine is capable of producing a significant reduction in total CSF SOD1 protein content in patients with ALS caused by different SOD1 mutations. Further long-term studies are warranted to assess clinical efficacy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-137645 (URN)10.1002/ana.24950 (DOI)000403795200009 ()28480639 (PubMedID)
Available from: 2017-07-18 Created: 2017-07-18 Last updated: 2018-06-09Bibliographically approved
Projects
Studies of enzymes metabolizing the toxic reduction products of oxygen the superoxide anion radical and hydrogen peroxide [2009-04942_VR]; Umeå UniversityMolecular structure of superoxide dismutase aggregates and pathogeneisis of amyotrophic lateral sclerosis [2012-01821_VR]; Umeå UniversityALS caused by strains of SOD1 prions [2015-02804_VR]; Umeå University
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-3270-2854

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