Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) associated with C9orf72 mutations. Here we identify a neuroprotective pathway of like-Sm protein 12 (Lsm12) and Exchange protein directly activated by cyclic AMP (Epac1) that suppresses NCT dysfunction by C9orf72-derived poly(glycine-arginine) proteins. Loss of Lsm12 function exacerbated neurodegeneration in Drosophila models of the poly(GR)-induced ALS/FTD. Consistently, Lsm12 depletion in human neuroblastoma cells enhanced the poly(GR)-induced impairment of NCT while promoting the formation of nuclear poly(GR) granules. Overexpression of ALS-associated Lsm12 mutant comparably strengthened the poly(GR) toxicity, indicating dominant-negative effects. Transcriptome analyses further revealed that Lsm12 up-regulates Epac1 expression whereas Epac1 overexpression rescued NCT defects in Lsm12-deleted cells. In fact, Epac1 depletion dissociated Ran/Importin β1 from cytoplasmic nucleopore complex, thereby dampening Ran gradient. These findings unveil a conserved role of the Lsm12-Epac1 pathway in the NCT-relevant pathogenesis of C9orf72-dependent ALS/FTD.