Effects of gem-dihydroperoxides against mutant copper‑zinc superoxide dismutase-mediated neurotoxicity

Publication date: Available online 5 September 2018Source: Molecular and Cellular NeuroscienceAuthor(s): Tomoyuki Ueda, Masatoshi Inden, Yuta Asaka, Yuji Masaki, Hisaka Kurita, Wakako Tanaka, Eiji Yamaguchi, Akichika Itoh, Isao HozumiAbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis, and death. Although its neuropathology is well investigated, currently, effective treatments are unavailable. The mechanism of ALS involves the aggregation and accumulation of several mutant proteins, including mutant copper‑zinc superoxide dismutase (SOD1), TAR DNA binding protein 43 kDa (TDP-43) and fused in sarcoma (FUS) proteins. Previous reports have shown that excessive oxidative stress, associated with mitochondrial dysfunction and mutant protein accumulation, contributes to ALS pathology. The present study focuses on the promotion of SOD1 misfolding and aggregation by oxidative stress. Having recently synthesized novel organic gem-dihydroperoxides (DHPs) with high anti-oxidant activity, we now examined whether DHPs reduce the mutant SOD1-induced intracellular aggregates involved in oxidative stress. We found that, among DHPs, 12AC2O significantly inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Moreover, immunofluorescence staining with redox-sensitive dyes showed that 12AC2O reduced the excessive level of intracellular mutant SOD1-induced reactive oxygen spe...
Source: Molecular and Cellular Neuroscience - Category: Neuroscience Source Type: research