Fluvoxamine restores TFEB-mediated autophagy through Sigma-1R-controlled POM121 expression

Abstract

Abstract Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two conditions that currently have no cure. Recent studies have shown that activation of the Sigma-1 receptor plays an important role in providing neuroprotection, particularly in ALS and Alzheimer’s disease. However, the mechanisms underlying Sigma-1R activation and its effect on (G4C2)n-RNA-induced cell death remain unclear. In this study, we demonstrated that fluvoxamine is a Sigma-1R agonist that can increase chaperone activity and rescue Pom121 intensity in (G4C2)31-RNA-expressing NSC34 cells, thereby stabilizing the protein expression of Pom121. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In C9orf72-ALS, the TFEB autophagy factor translocation decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted TFEB translocation into the nucleus and increased LC3-II expression compared to the overexpression of (G4C2)31-RNA alone. Collectively, fluvoxamine may act as a promising repurposed medicine for patients with C9orf72-ALS, as it stabilizes the nucleoporin Pom121 and promotes the translocation of TFEB in (G4C2)31-RNA-expressing NSC34 cells.