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

Sigma-1 receptor (Sig-1R) acts as a molecular chaperone that rescues nucleocytoplasmic transport defects caused by C9orf72 (G4C2)-RNA repeat expansions in ALS and frontotemporal dementia (FTD) models. The study links the pathology to the (G4C2)-RNA repeats binding the Ran-activating protein RanGAP at the nuclear pore, which contributes to cytosolic accumulation of Ran and impaired transport. In cell lines, Sig-1R colocalizes with RanGAP and nuclear pore proteins, stabilizes nucleoporins, and directly binds (G4C2)-RNA repeats. Overexpressing Sig-1R reverses the aberrant Ran distribution, while knocking out Sig-1R worsens it, supporting a functional, target-at-the-nuclear-pore mechanism. In Drosophila, Sig-1R overexpression (but not an E102Q mutant) reverses deficits including eye necrosis, climbing impairment, and electrophysiological abnormalities. Overall, the work suggests Sig-1R could benefit C9orf72 ALS/FTD by chaperoning nuclear pore assembly and sequestering toxic RNA repeats.