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

• Published in: Nature communications 2020-11, Vol.11 (1), p.5580-5580, Article 5580
• Main Authors: Lee, Pin-Tse, Liévens, Jean-Charles, Wang, Shao-Ming, Chuang, Jian-Ying, Khalil, Bilal, Wu, Hsiang-en, Chang, Wen-Chang, Maurice, Tangui, Su, Tsung-Ping
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 13/109; 13/44; 13/51; 13/89; 13/95; 14; 14/1; 14/19; 14/35; 42; 42/35; 42/44; 631/378; 631/80/304; 64; 64/24; 82/29; 82/83; 96; 96/95; Accumulation; Active Transport, Cell Nucleus - genetics; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Cell lines; Chaperones; Chromosomes; Cytosol; Cytosol - metabolism; Dementia disorders; Disease Models, Animal; Drosophila; Drosophila - genetics; Drosophila - metabolism; Drosophila - physiology; Frontotemporal dementia; Frontotemporal Dementia - genetics; Frontotemporal Dementia - metabolism; Fruit flies; Gene Knockout Techniques; HeLa Cells; Humanities and Social Sciences; Humans; Insects; Life Sciences; Motor Neurons - metabolism; multidisciplinary; Necrosis; Neurobiology; Neurons and Cognition; Nuclear Pore - genetics; Nuclear Pore - metabolism; Pathological effects; Protein Binding; Proteins; ran GTP-Binding Protein - genetics; ran GTP-Binding Protein - metabolism; Receptors; Receptors, sigma - genetics; Receptors, sigma - metabolism; Ribonucleic acid; RNA; RNA, Small Interfering; Science; Science (multidisciplinary); Sigma-1 Receptor; Subgroups
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19396-3

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. The (G4C2)-RNA hexanucleotide repeat expansion upstream of the start codon of the C9orf72 gene plays a critical role in familial ALS. The authors show that Sig1R, a ligand-regulated molecular chaperone, counteracts the aberrant nucleocytoplasmic distribution of Ran caused by the (G4C2)-RNA repeats.