Fluvoxamine Exerts Sigma-1R to Rescue Autophagy via Pom121-Mediated Nucleocytoplasmic Transport of TFEB
Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alz...
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Veröffentlicht in: | Molecular neurobiology 2024-08, Vol.61 (8), p.5282-5294 |
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Sprache: | eng |
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Zusammenfassung: | Expansion of the GGGGCC-RNA repeat is a known cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), which currently have no cure. Recent studies have indicated the activation of Sigma-1 receptor plays an important role in providing neuroprotection, especially in ALS and Alzheimer’s disease. Nevertheless, the mechanisms underlying Sigma-1R activation and its effect on (G
4
C
2
)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 stabilize the protein expression of Pom121 in (G
4
C
2
)
31
-RNA-expressing NSC34 cells, leading to increased colocalization at the nuclear envelope. Interestingly, fluvoxamine treatment increased Pom121 protein expression without affecting transcription. In
C9orf72
-ALS, the nuclear translocation of TFEB autophagy factor decreased owing to nucleocytoplasmic transport defects. Our results showed that pretreatment of NSC34 cells with fluvoxamine promoted the shuttling of TFEB into the nucleus and elevated the expression of LC3-II compared to the overexpression of (G
4
C
2
)
31
-RNA alone. Additionally, even when used alone, fluvoxamine increases Pom121 expression and TFEB translocation. To summarize, 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 (G
4
C
2
)
31
-RNA-expressing NSC34 cells. |
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ISSN: | 0893-7648 1559-1182 1559-1182 |
DOI: | 10.1007/s12035-023-03885-9 |