Cellular Pathobiology Section, Integrative Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, NIH, 333 Cassell Drive, Baltimore, MD, 21224, USA.
The Ph.D Program for Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
Nat Commun. 2020 Nov 4;11(1):5580. doi: 10.1038/s41467-020-19396-3.
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.
在肌萎缩性侧索硬化症（ALS）/额颞叶痴呆（FTD）的患者亚群中，C9orf72 染色体上的（G4C2）-RNA 重复序列与核孔中的 Ran 激活蛋白（RanGAP）结合，导致核质转运缺陷和细胞质中 Ran 的积累。在这里，我们发现 sigma-1 受体（Sig-1R），一种分子伴侣，可逆转细胞系和果蝇中（G4C2）-RNA 重复序列的病理作用。Sig-1R 与 RanGAP 和核孔蛋白（Nups）共定位，并稳定后者。有趣的是，Sig-1Rs 直接与（G4C2）-RNA 重复序列结合。Sig-1Rs 的过表达可挽救（G4C2）-RNA 重复序列诱导的 Ran 异常细胞质积累，而 Sig-1R 的敲除则加剧了这一过程。在果蝇中，Sig-1R（而非 Sig-1R-E102Q 突变体）的过表达可逆转（G4C2）-RNA 重复序列引起的眼睛坏死、攀爬缺陷和放电释放。这些核孔处分子伴侣的研究结果表明，Sig-1Rs 可能通过伴侣核孔组装并吸收有害的（G4C2）-RNA 重复序列，从而使 C9orf72 ALS/FTD 患者受益。
