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

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.

Nuclear pore dysfunction and disease: a complex opportunity

“…The pathology of neurodegenerative disease compromises many biological processes, and thus it may be productive to investigate ancillary pathways, such as autophagy, to address issues in NPC homeostasis. To this end, several groups have studied the cytoplasmic mislocalization of the autophagic transcription factor, TFEB [ 94 , 116 , 344 , 345 ]. TFEB regulates the expression of lysosomal proteins, and studies in brain tissue from AD and ALS patients showed that this protein was mislocalized in disease [ 116 ], indicating convergence between defects in NCT and autophagy.…”

“…Additionally, Sigmar1 overexpression restores Kapβ1-mediated nuclear import of TFEB, promoting autophagy [ 94 ]. Moreover, two Sigmar1 agonists, pridopidine and fluvoxamine, each promote POM121 expression and restore TFEB nuclear localization, and pridopidine protects against cell death [ 94 , 345 ]. Encouragingly, pridopidine has also been identified to have therapeutic potential in AD [ 347 ], PD [ 348 ], and HD [ 349 ].…”