Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models

Pin-Tse Lee, Jean-Charles Liévens, Shao-Ming Wang, Jian-Ying Chuang, Bilal Khalil, Hsiang-en Wu, Wen-Chang Chang, Tangui Maurice and Tsung-Ping Su ()
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Pin-Tse Lee: National Institute on Drug Abuse
Jean-Charles Liévens: University of Montpellier, EPHE, INSERM
Shao-Ming Wang: National Institute on Drug Abuse
Jian-Ying Chuang: Taipei Medical University
Bilal Khalil: Mayo Clinic
Hsiang-en Wu: National Institute on Drug Abuse
Wen-Chang Chang: Taipei Medical University
Tangui Maurice: University of Montpellier, EPHE, INSERM
Tsung-Ping Su: National Institute on Drug Abuse

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: ABSTRACT In a subgroup of patients with amyotrophic lateral sclerosis (ALS)/Frontotemporal dementia (FTD), the (G4C2)-RNA repeat expansion from C9orf72 chromosome binds to the Ran-activating protein (RanGAP) at the nuclear pore, resulting in nucleocytoplasmic transport deficit and accumulation of Ran in the cytosol. Here, we found that the sigma-1 receptor (Sig-1R), a molecular chaperone, reverses the pathological effects of (G4C2)-RNA repeats in cell lines and in Drosophila. The Sig-1R colocalizes with RanGAP and nuclear pore proteins (Nups) and stabilizes the latter. Interestingly, Sig-1Rs directly bind (G4C2)-RNA repeats. Overexpression of Sig-1Rs rescues, whereas the Sig-1R knockout exacerbates, the (G4C2)-RNA repeats-induced aberrant cytoplasmic accumulation of Ran. In Drosophila, Sig-1R (but not the Sig-1R-E102Q mutant) overexpression reverses eye necrosis, climbing deficit, and firing discharge caused by (G4C2)-RNA repeats. These results on a molecular chaperone at the nuclear pore suggest that Sig-1Rs may benefit patients with C9orf72 ALS/FTD by chaperoning the nuclear pore assembly and sponging away deleterious (G4C2)-RNA repeats.

Date: 2020
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DOI: 10.1038/s41467-020-19396-3

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