Cellular analysis of SOD1 protein-aggregation propensity and toxicity: a case of ALS with slow progression harboring homozygous SOD1-D92G mutation

Abstract

Mutations within Superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS), accounting for approximately 20% of familial cases. The pathological feature is a loss of motor neurons with enhanced formation of intracellular misfolded SOD1. Homozygous SOD1-D90A in familial ALS has been reported to show slow disease progression. Here, we reported a rare case of a slowly progressive ALS patient harboring a novel SOD1 homozygous mutation D92G (homD92G). The neuronal cell line overexpressing SOD1-D92G showed a lower ratio of the insoluble/soluble fraction of SOD1 with fine aggregates of the misfolded SOD1 and lower cellular toxicity than those overexpressing SOD1-G93A, a mutation that generally causes rapid disease progression. Next, we analyzed spinal motor neurons derived from induced pluripotent stem cells (iPSC) of a healthy control subject and ALS patients carrying SOD1-homD92G or heterozygous SOD1-L144FVX mutation. Lower levels of misfolded SOD1 and cell loss were observed in the motor neurons differentiated from patient-derived iPSCs carrying SOD1-homD92G than in those carrying SOD1-L144FVX. Taken together, SOD1-homD92G has a lower propensity to aggregate and induce cellular toxicity than SOD1-G93A or SOD1-L144FVX, and these cellular phenotypes could be associated with the clinical course of slowly progressive ALS.

Updates on Disease Mechanisms and Therapeutics for Amyotrophic Lateral Sclerosis

“…A wide range of clinical symptoms were observed in ALS cases carrying SOD1 mutations, from the classic ALS phenotypes with the involvement of upper and lower motor neurons to progressive muscular atrophy to mixed phenotypes of ALS and neurodegenerative diseases [ 15 ]. Specific SOD1 mutations were found to be associated with distinct clinical phenotypes [ 35 , 36 , 37 , 38 ]. For example, the G41S mutation showed a significantly shorter survival time and faster progression while the L144S SOD1 mutation showed a longer survival and slower disease progression compared to other tested mutations, such as K3E, L126* and N139D [ 15 ].…”

“…The SOD1-G93A mice developed SOD1 protein aggregates in motor neurons that recapitulated the pathological hallmark in most SOD1 ALS patients. The mutations, including homozygous D92G- SOD1 , showed less aggregates and a lower toxicity compared to G93A- SOD1 or L1144FVX- SOD1 , and were linked with less severe disease in patients [ 35 ]. In contrast, SOD1 knockout mice developed normally with no overt motor phenotypes by 6 months of age and no sign of disease pathology by 4 months of age.…”