The motor system is exceptionally vulnerable to absence of the ubiquitously expressed superoxide dismutase-1
Standard
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
APA
Vancouver
Bibtex
}
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 -