Author:

Keywords:

Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, NUCLEAR-PORE COMPLEX, REPEAT EXPANSION, MOUSE MODEL, HEXANUCLEOTIDE REPEAT, COCAINE BINDING, PC12 CELLS, C9ORF72, NEURODEGENERATION, DYSFUNCTION, ACTIVATION, Active Transport, Cell Nucleus, Amyotrophic Lateral Sclerosis, Animals, Cytosol, Disease Models, Animal, Drosophila, Frontotemporal Dementia, Gene Knockout Techniques, HeLa Cells, Humans, Motor Neurons, Nuclear Pore, Protein Binding, RNA, Small Interfering, Receptors, sigma, ran GTP-Binding Protein, Sigma-1 Receptor, Hela Cells

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.