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The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1

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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.

In: BRAIN COMMUN, Vol. 5, No. 1, 2023, p. fcad017.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Park, JH, Nordström, U, Tsiakas, K, Keskin, I, Elpers, C, Mannil, M, Heller, R, Nolan, M, Alburaiky, S, Zetterström, P, Hempel, M, Schara-Schmidt, U, Biskup, S, Steinacker, P, Otto, M, Weishaupt, J, Hahn, A, Santer, R, Marquardt, T, Marklund, SL & Andersen, PM 2023, 'The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1', BRAIN COMMUN, vol. 5, no. 1, pp. fcad017. https://doi.org/10.1093/braincomms/fcad017

APA

Park, J. H., Nordström, U., Tsiakas, K., Keskin, I., Elpers, C., Mannil, M., Heller, R., Nolan, M., Alburaiky, S., Zetterström, P., Hempel, M., Schara-Schmidt, U., Biskup, S., Steinacker, P., Otto, M., Weishaupt, J., Hahn, A., Santer, R., Marquardt, T., ... Andersen, P. M. (2023). The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1. BRAIN COMMUN, 5(1), fcad017. https://doi.org/10.1093/braincomms/fcad017

Vancouver

Park JH, Nordström U, Tsiakas K, Keskin I, Elpers C, Mannil M et al. The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1. BRAIN COMMUN. 2023;5(1):fcad017. https://doi.org/10.1093/braincomms/fcad017

Bibtex

@article{0edb944e62894f5594f7fb81d9394632,
title = "The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1",
abstract = "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.",
author = "Park, {Julien H} and Ulrika Nordstr{\"o}m and Konstantinos Tsiakas and Isil Keskin and Christiane Elpers and Manoj Mannil and Raoul Heller and Melinda Nolan and Salam Alburaiky and Per Zetterstr{\"o}m and Maja Hempel and Ulrike Schara-Schmidt and Saskia Biskup and Petra Steinacker and Markus Otto and Jochen Weishaupt and Andreas Hahn and Ren{\'e} Santer and Thorsten Marquardt and Marklund, {Stefan L} and Andersen, {Peter M}",
note = "{\textcopyright} The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.",
year = "2023",
doi = "10.1093/braincomms/fcad017",
language = "English",
volume = "5",
pages = "fcad017",
journal = "BRAIN COMMUN",
issn = "2632-1297",
publisher = "OXFORD UNIV PRESS",
number = "1",

}

RIS

TY - JOUR

T1 - The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1

AU - Park, Julien H

AU - Nordström, Ulrika

AU - Tsiakas, Konstantinos

AU - Keskin, Isil

AU - Elpers, Christiane

AU - Mannil, Manoj

AU - Heller, Raoul

AU - Nolan, Melinda

AU - Alburaiky, Salam

AU - Zetterström, Per

AU - Hempel, Maja

AU - Schara-Schmidt, Ulrike

AU - Biskup, Saskia

AU - Steinacker, Petra

AU - Otto, Markus

AU - Weishaupt, Jochen

AU - Hahn, Andreas

AU - Santer, René

AU - Marquardt, Thorsten

AU - Marklund, Stefan L

AU - Andersen, Peter M

N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2023

Y1 - 2023

N2 - 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.

AB - 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.

U2 - 10.1093/braincomms/fcad017

DO - 10.1093/braincomms/fcad017

M3 - SCORING: Journal article

C2 - 36793789

VL - 5

SP - fcad017

JO - BRAIN COMMUN

JF - BRAIN COMMUN

SN - 2632-1297

IS - 1

ER -