C9ORF72ジペプチドによるミトコンドリア蛋白翻訳抑制機構の解明

抄録

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease for which no curative treatment is established. Recently, it has been proposed that insufficient energy production due to mitochondrial dysfunction may underlie the ALS pathogenesis, but the precise mechanism remains to be elucidated. Mutant C9ORF72, the most common ALS-causative gene, produces five dipeptide repeat proteins from the abnormally elongated (GGGGCC) sequence. Among them, poly(GR) has been shown to affect mitochondrial function and impair energy production via unknown mechanisms. We focused on the fact that mitochondria have a translation mechanism similar to that of prokaryotes. The newly synthesized mitochondrial proteins can be visualized using the click chemistry technique under cycloheximide treatment because mitochondrial translation is resistant to cycloheximide. We found that poly(GR) strongly inhibited mitochondrial translation, whereas poly(PR), another Arg-rich C9ORF72-dipeptide, did not. We also found that poly(GR) activated mitochondrial UPR (UPRmt) signaling, especially the ATF4/CHOP axis. Therefore, we speculated that aberrant activation of UPRmt by poly(GR) suppresses mitochondrial translation, leading to insufficient mitochondrial energy production and motor neuronal cell death.