The study investigates the impact of the C9ORF72 repeat expansion, specifically the GGGGCC (G4C2) hexanucleotide repeat, on nucleocytoplasmic transport in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The research identifies RanGAP1 as a key regulator of nucleocytoplasmic transport that is disrupted by the G4C2 repeat expansion. RanGAP1 physically interacts with the G4C2 RNA and is mislocalized in flies expressing 30 G4C2 repeats, as well as in C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSNs) and brain tissue from C9ORF72 ALS patients. The disruption of RanGAP1 function impairs nuclear import, leading to defects in protein localization and neurodegeneration. Small molecules and antisense oligonucleotides targeting the G4C2 G-quadruplexes rescue these defects, suggesting a potential therapeutic strategy for ALS and FTD. The study also highlights the importance of nucleocytoplasmic transport in the pathogenesis of these diseases and the potential for pharmacological intervention.The study investigates the impact of the C9ORF72 repeat expansion, specifically the GGGGCC (G4C2) hexanucleotide repeat, on nucleocytoplasmic transport in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The research identifies RanGAP1 as a key regulator of nucleocytoplasmic transport that is disrupted by the G4C2 repeat expansion. RanGAP1 physically interacts with the G4C2 RNA and is mislocalized in flies expressing 30 G4C2 repeats, as well as in C9ORF72 ALS patient-derived induced pluripotent stem cells (iPSNs) and brain tissue from C9ORF72 ALS patients. The disruption of RanGAP1 function impairs nuclear import, leading to defects in protein localization and neurodegeneration. Small molecules and antisense oligonucleotides targeting the G4C2 G-quadruplexes rescue these defects, suggesting a potential therapeutic strategy for ALS and FTD. The study also highlights the importance of nucleocytoplasmic transport in the pathogenesis of these diseases and the potential for pharmacological intervention.