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

@article{Lee:2020aab,

title = {Sigma-1 receptor chaperones rescue nucleocytoplasmic transport deficit seen in cellular and Drosophila ALS/FTD models},

author = {Pin-Tse Lee and Jean-Charles Liévens and Shao-Ming Wang and Jian-Ying Chuang and Bilal Khalil and Hsiang-en Wu and Wen-Chang Chang and Tangui Maurice and Tsung-Ping Su},

url = {https://pubmed.ncbi.nlm.nih.gov/33149115/},

doi = {10.1038/s41467-020-19396-3},

isbn = {2041-1723},

year  = {2020},

date = {2020-01-01},

journal = {Nature Communications},

volume = {11},

number = {1},

pages = {5580},

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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}