Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with higher selectivity in degeneration of motor neurons. However, the molecular mechanism by which the ALS-linked mutants of human superoxide dismutase 1 (SOD1) gene induce neurotoxicity remains obscure yet. Here, we show that depletion of CIIA expression by RNA interference (RNAi) promoted cytotoxicity caused by ALS-linked G93A mutant of the SOD1 gene. The RNAi-mediated knockdown of CIIA also enhanced the SOD1(G93A)-induced interaction between ASK1 and TRAF2 as well as ASK1 activity. Furthermore, endogenous silencing of CIIA by RNAi augmented the effects of SOD1(G93A) on reduction of mitochondria membrane potential (Δψm), release of cytochrome c into the cytoplasm, and caspase activation. Together, our results suggest that CIIA negatively modulates ASK1-mediated cytotoxic signaling processes in a SOD1(G93A)-expressing cellular model of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with higher selectivity in degeneration of upper and lower motor neurons
Given that apoptosis signal-regulating kinase 1 (ASK1) contributes to neurodegeneration in ALS, we investigated the possible role of caspase-activated DNase inhibitor that interacts with ASK1 (CIIA) in the regulation of ASK1-mediated signaling initiated by superoxide dismnutase-1 (SOD1)(G93A)
CIIA SUPPRESSES SOD1(G93A)-INDUCED CYTOTOXICITY Given that CIIA has been shown to prevent apoptotic cell death induced by various cellular stresses including oxidative stress (Cho et al, 2003), we examined whether CIIA affects SOD1(G93A)-induced apoptosis
Summary
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease with higher selectivity in degeneration of upper and lower motor neurons. These results suggest that CIIA functions as a negative modulator of ASK1-mediated cytotoxic signaling processes in SOD1(G93A)expressing cellular model of ALS. Depletion of CIIA expression by RNA interference (RNAi) enhanced SOD1(G93A)-induced apoptosis in Neuro2A (N2a) cells (Figure 1A).
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