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The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences. Department of General Paediatrics, University of Münster, Münster, Germany.ORCID iD: 0000-0003-2305-9948
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Neurosciences.ORCID iD: 0000-0002-7757-2344
Department of Paediatrics, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2023 (English)In: Brain Communications, E-ISSN 2632-1297, Vol. 5, no 1, article id fcad017Article in journal (Refereed) Published
Abstract [en]

Superoxide dismutase-1 is a ubiquitously expressed antioxidant enzyme. Mutations in SOD1 can cause amyotrophic lateral sclerosis, probably via a toxic gain-of-function involving protein aggregation and prion-like mechanisms. Recently, homozygosity for loss-of-function mutations in SOD1 has been reported in patients presenting with infantile-onset motor neuron disease. We explored the bodily effects of superoxide dismutase-1 enzymatic deficiency in eight children homozygous for the p.C112Wfs∗11 truncating mutation. In addition to physical and imaging examinations, we collected blood, urine and skin fibroblast samples. We used a comprehensive panel of clinically established analyses to assess organ function and analysed oxidative stress markers, antioxidant compounds, and the characteristics of the mutant Superoxide dismutase-1. From around 8 months of age, all patients exhibited progressive signs of both upper and lower motor neuron dysfunction, cerebellar, brain stem, and frontal lobe atrophy and elevated plasma neurofilament concentration indicating ongoing axonal damage. The disease progression seemed to slow down over the following years. The p.C112Wfs∗11 gene product is unstable, rapidly degraded and no aggregates were found in fibroblast. Most laboratory tests indicated normal organ integrity and only a few modest deviations were found. The patients displayed anaemia with shortened survival of erythrocytes containing decreased levels of reduced glutathione. A variety of other antioxidants and oxidant damage markers were within normal range. In conclusion, non-neuronal organs in humans show a remarkable tolerance to absence of Superoxide dismutase-1 enzymatic activity. The study highlights the enigmatic specific vulnerability of the motor system to both gain-of-function mutations in SOD1 and loss of the enzyme as in the here depicted infantile superoxide dismutase-1 deficiency syndrome.

Place, publisher, year, edition, pages
Oxford University Press, 2023. Vol. 5, no 1, article id fcad017
Keywords [en]
ALS, infantile motor neuron disease, oxygen toxicity, SOD1, spasticity
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-208224DOI: 10.1093/braincomms/fcad017ISI: 000929911200001PubMedID: 36793789Scopus ID: 2-s2.0-85153953022OAI: oai:DiVA.org:umu-208224DiVA, id: diva2:1756523
Funder
The Swedish Brain Foundation, 2016-0303The Swedish Brain Foundation, 2018-0310The Swedish Brain Foundation, 2020-0353Swedish Research Council, 2017-03100Knut and Alice Wallenberg Foundation, 2012.0091Knut and Alice Wallenberg Foundation, 2014.0305Knut and Alice Wallenberg Foundation, 2020.0232Umeå UniversityRegion VästerbottenKonung Gustaf V:s och Drottning Victorias FrimurarestiftelseAvailable from: 2023-05-12 Created: 2023-05-12 Last updated: 2023-05-12Bibliographically approved

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Park, Julien H.Nordström, UlrikaKeskin, IsilZetterström, PerMarklund, Stefan L.Andersen, Peter M.

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