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The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1
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 repo...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924500/ https://www.ncbi.nlm.nih.gov/pubmed/36793789 http://dx.doi.org/10.1093/braincomms/fcad017 |
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author | Park, Julien H Nordström, Ulrika Tsiakas, Konstantinos Keskin, Isil Elpers, Christiane Mannil, Manoj Heller, Raoul Nolan, Melinda Alburaiky, Salam Zetterström, Per Hempel, Maja Schara-Schmidt, Ulrike Biskup, Saskia Steinacker, Petra Otto, Markus Weishaupt, Jochen Hahn, Andreas Santer, René Marquardt, Thorsten Marklund, Stefan L Andersen, Peter M |
author_facet | Park, Julien H Nordström, Ulrika Tsiakas, Konstantinos Keskin, Isil Elpers, Christiane Mannil, Manoj Heller, Raoul Nolan, Melinda Alburaiky, Salam Zetterström, Per Hempel, Maja Schara-Schmidt, Ulrike Biskup, Saskia Steinacker, Petra Otto, Markus Weishaupt, Jochen Hahn, Andreas Santer, René Marquardt, Thorsten Marklund, Stefan L Andersen, Peter M |
author_sort | Park, Julien H |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9924500 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-99245002023-02-14 The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 Park, Julien H Nordström, Ulrika Tsiakas, Konstantinos Keskin, Isil Elpers, Christiane Mannil, Manoj Heller, Raoul Nolan, Melinda Alburaiky, Salam Zetterström, Per Hempel, Maja Schara-Schmidt, Ulrike Biskup, Saskia Steinacker, Petra Otto, Markus Weishaupt, Jochen Hahn, Andreas Santer, René Marquardt, Thorsten Marklund, Stefan L Andersen, Peter M Brain Commun Original Article 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. Oxford University Press 2023-01-27 /pmc/articles/PMC9924500/ /pubmed/36793789 http://dx.doi.org/10.1093/braincomms/fcad017 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Article Park, Julien H Nordström, Ulrika Tsiakas, Konstantinos Keskin, Isil Elpers, Christiane Mannil, Manoj Heller, Raoul Nolan, Melinda Alburaiky, Salam Zetterström, Per Hempel, Maja Schara-Schmidt, Ulrike Biskup, Saskia Steinacker, Petra Otto, Markus Weishaupt, Jochen Hahn, Andreas Santer, René Marquardt, Thorsten Marklund, Stefan L Andersen, Peter M The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title | The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title_full | The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title_fullStr | The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title_full_unstemmed | The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title_short | The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
title_sort | motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9924500/ https://www.ncbi.nlm.nih.gov/pubmed/36793789 http://dx.doi.org/10.1093/braincomms/fcad017 |
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