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Widespread CNS pathology in amyotrophic lateral sclerosis homozygous for the D90A SOD1 mutation
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0003-2911-6026
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2023 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 145, no 1, p. 13-28Article in journal (Refereed) Published
Abstract [en]

Mutations in the gene encoding the ubiquitously expressed free radical scavenging enzyme superoxide dismutase-1 (SOD1) are found in 2–6% of amyotrophic lateral sclerosis patients. The most frequent SOD1 mutation worldwide is D90A. Amyotrophic lateral sclerosis caused by this mutation has some unusual features: the heredity is usually recessive, the phenotype is stereotypic with slowly evolving motor symptoms beginning in the legs and may also include sensory, autonomic, and urinary bladder involvement. Furthermore, the mutant protein resembles the wild type, with normal content and enzymatic activity in the central nervous system. Here, we report neuropathological findings in nine patients homozygous for the D90A mutation. All nine had numerous small granular inclusions immunoreactive for misfolded SOD1 in motor neurons and glial nuclei in the spinal cord and brainstem. In addition to degeneration of the corticospinal tracts, all patients had degeneration of the dorsal columns. We also found intense gliosis in circumscribed cortical areas of the frontal and temporal lobes and in the insula. In these areas and in adjacent white matter, there were SOD1 staining neuropil threads. A few SOD1-immunopositive cytoplasmic neuronal inclusions were observed in cortical areas, as were glial nuclear inclusions. As suggested by the symptoms and signs and earlier neurophysiological and imaging investigations, the histopathology in patients homozygous for the D90A SOD1 extends beyond the motor system to include cognitive and sensory cortical areas. However, even in the patients that had a symptomatic disease duration of more than 2 or 3 decades and lived into their 70s or 80s, there were no SOD1-inclusion pathology and no typical dysfunction (apart from the musculature) in non-nervous organs. Thus, only specific parts of the CNS seem to be vulnerable to toxicity provoked by homozygously expressed mutant SOD1.

Place, publisher, year, edition, pages
Springer-Verlag New York, 2023. Vol. 145, no 1, p. 13-28
Keywords [en]
Amyotrophic lateral sclerosis, D90A, Human autopsy, Neuronal inclusions, Superoxide dismutase-1
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-201353DOI: 10.1007/s00401-022-02519-zISI: 000884616800001PubMedID: 36385230Scopus ID: 2-s2.0-85142073549OAI: oai:DiVA.org:umu-201353DiVA, id: diva2:1717504
Funder
The Swedish Brain Foundation, 2012- 0262The Swedish Brain Foundation, 2012-0305The Swedish Brain Foundation, 2013-0279The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2019-0320The Swedish Brain Foundation, 2020-0353The Swedish Brain Foundation, 2021-0402Swedish Research Council, 2009-3548Swedish Research Council, 2012-3167Swedish Research Council, 2017-03100Swedish Research Council, 2019-01707Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, d 2020.0232The Kempe FoundationsRegion Västerbotten, 2013-7590Region Västerbotten, 56103-7002829Region Västerbotten, RV-841161Region Västerbotten, RV-833421Region Västerbotten, RV-932195Region Västerbotten, RV-939329Region Västerbotten, RV-941598Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseAvailable from: 2022-12-08 Created: 2022-12-08 Last updated: 2023-01-11Bibliographically approved

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Forsberg, KarinGraffmo, Karin SixtensdotterStenvall, EricaMarklund, Stefan L.Brännström, ThomasAndersen, Peter M.

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