Mutant superoxide dismutase-1 indistinguishable from wild-type causes ALS

Abstract

A reason for screening amyotrophic lateral sclerosis (ALS) patients for mutations in the superoxide dismutase-1 (SOD1) gene is the opportunity to find novel mutations with properties that can give information on pathogenesis. A novel c.352C>G (L117V) SOD1 mutation was found in two Syrian ALS families living in Europe. The disease showed unusually low penetrance and slow progression. In erythrocytes, the total SOD1 activity, as well as specific activity of the mutant protein, was equal in carriers of the mutation and family controls lacking SOD1 mutations. The structural stabilities of the L117V mutant and wild-type SOD1 under denaturing conditions were likewise equal, but considerably lower than that of murine SOD1. As analyzed with an ELISA specific for misfolded SOD1 species, no differences were found in the content of misfolded SOD1 protein between extracts of fibroblasts from wild-type controls and from an L117V patient. In contrast, elevated levels of misfolded SOD1 protein were found in fibroblasts from ALS patients carrying seven other mutations in the SOD1 gene. We conclude that mutations in SOD1 that result in a fully stable protein are associated with low disease penetrance for ALS and may be found in cases of apparently sporadic ALS. Wild-type human SOD1 is moderately stable, and was found here to be within the stability range of ALS-causing SOD1 variants, lending support to the hypothesis that wild-type SOD1 could be more generally involved in ALS pathogenesis.

Neuron-Microglia Interactions in Motor Neuron Degeneration. The Inflammatory Hypothesis in Amyotrophic Lateral Sclerosis Revisited

“…Characterized in motor neurons and glial cells, wild-type and mutant SOD1 aggregates [39,48] correlate with a similar ALS phenotype [49,50] and also in mice with wild-type SOD1 causing ALS [51]. Inflammation and neuronal death represent a cascade events that are also present in other neurodegenerative diseases characterized by misfolded protein aggregates like the protease-resistant prion protein, Amyloid-β, Tau, or α-synuclein [52,53].…”

The Disulfide Bond, but Not Zinc or Dimerization, Controls Initiation and Seeded Growth in Amyotrophic Lateral Sclerosis-linked Cu,Zn Superoxide Dismutase (SOD1) Fibrillation

“…It is important to remember that the identity of the toxic species is unknown; hence, the relative contributions of spontaneous fibrillation versus seeded amyloid formation to this process are unclear. Recent observations that not all ALS mutations are fully penetrant (66) and that overexpression of wild-type human SOD1 in mice leads to ALS symptoms (15) highlight the stochastic nature of initiation of disease and the potential for wild-type human SOD1 to play a role in sporadic cases of ALS.…”

IL-10 Controls Early Microglial Phenotypes and Disease Onset in ALS Caused by Misfolded Superoxide Dismutase 1

“…Increasing evidence suggests that misfolded SOD1 (mSOD1) species common for all mutations may be secreted and involved in cytotoxicity (Urushitani et al, 2006;Zetterström et al, 2011;Grad et al, 2014). Furthermore, using conformation-specific antibodies, the misfolded SOD1 species have been detected in CSF and spinal cords of sporadic ALS patients, potentially suggesting a common SOD1-dependent pathogenic mechanism in ALS (Bosco et al, 2010;Zetterström et al, 2011;Synofzik et al, 2012).…”