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, nonneuronal 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.

Relation Between Reactive Oxygen Species Production and Transient Receptor Potential Vanilloid1 Expression in Human Skin During Aging

“…In order to investigate whether oxidative stress affect mast cell degranulation in skin aging-related alterations and whether endogenous antioxidants are sufficient to counteract skin cell stress injury, we evaluated levels of both ROS and SOD-1, a ubiquitously expressed antioxidant enzyme. 62 We observed that skin ROS levels were more pronounced in elderly specimens when compared to adult specimens (Fig. 2A).…”

Targeting low levels of MIF expression as a potential therapeutic strategy for ALS

“…Fortunately for SOD1 familial ALS (fALS) patients, the intrathecally administered antisense oligonucleotide that reduces synthesis of the SOD1 protein 41 , 75 , 76 was recently approved by the US Food and Drug Administration (FDA). While downregulation of SOD1 can be effective in SOD1 fALS, its long-term effects must be carefully monitored so that the protein does not reach a critically low expression level, 77 , 78 , 79 and, for all other forms of fALS/sALS, efficient disease modifying therapies are urgently needed.…”

SOD1 Enzymatic Activity in CSF from ALS patients with and withoutSOD1mutations

“…Disordered proteins are efficiently recognized for degradation and there is no synthesis of new protein. As a result, the amounts of mutant SOD1 in erythrocytes vary widely depending on the degrees of destabilization, from close to the wildtype protein to <0.1% (Ezer et al, 2022; Jonsson et al, 2002; Park et al, 2023; Sato et al, 2005). The remaining mutant SOD1 protein is likely to mostly be active, resulting in SOD1 activities in heterozygotes varying from half to equal of controls (Keskin et al, 2017).…”

“…Further emphasizing the importance of SOD1 activity and indicating vulnerability to low SOD1 levels in the CNS is the recent discovery of children homozygous for SOD1 mutations that result in total-loss-of enzymatic function. These children are born normal but develop, from about the age of 6 months, the Infantile SOD Deficiency Syndrome (ISODDES) with progressive affection of both the upper and lower motor neuron systems but also with additional neurological and hematological abnormalities (Andersen et al, 2019; Çakar et al, 2023; de Souza et al, 2021; Dogan et al, 2024; Ezer et al, 2022; Park et al, 2023). So far, homozygosity for four SOD1 mutations has been associated with causing ISODDES.…”