Abstract
SOD1 mutations account for ∼20% of familial amyotrophic lateral sclerosis (ALS) cases in which the hallmark pathological feature is insoluble SOD1 aggregates within motor neurons. Here, we investigated the degradation and synthesis of mutant SOD1 to determine whether the aggregation of mutant SOD1A4V affects these processes. We confirm that, in general, the degradation of mutant SOD1A4V occurs at a significantly faster rate than wild-type SOD1. We also report that the turnover and synthesis of mutant SOD1A4V is impaired in the presence of insoluble SOD1A4V aggregates. However, the timing of aggregation of SOD1A4V did not coincide with UPS dysfunction. Together, these results reveal the impact of SOD1 aggregation on protein degradation pathways, highlighting the importance of the UPS in preventing neurodegenerative disorders such as ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the progressive loss of motor neurons in the brain and spinal cord
Consistent with previous reports, we found that the turnover of mutant SOD1A4V-Dendra2 was faster in NSC-34 cells than SOD1WT-Dendra2 (Figure 1B), with SOD1A4V-Dendra2 exhibiting a significantly shorter half-life (∼7 h) compared to SOD1WT-Dendra2 (∼17 h) (Figure 1C)
We demonstrate that the aggregation of mutant SOD1A4V impairs the turnover and synthesis of mutant superoxide dismutase 1 (SOD1) protein
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterised by the progressive loss of motor neurons in the brain and spinal cord. Dominant missense mutations in the gene encoding superoxide dismutase 1 (SOD1) were the first discovered to cause ALS, and account for approximately 20% of all fALS cases and up to 50% in China. Consistent with a collapse in proteome homeostasis, the pathology of ALS is characterised by the deposition of ubiquitinated protein inclusions within motor neurons (Leigh et al, 1991). The composition of these inclusions is heterogeneous, and the primary constituent varies depending on the disease subtype (sALS or fALS), and the underlying gene mutation. While SOD1 fALS cases show exclusive deposition of SOD1, inclusions contain proteins associated with quality control machinery and other unrelated aggregation-prone or supersaturated proteins
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