Lsm12-Epac1 pathway suppresses C9orf72 poly(GR)-induced neurodegeneration by establishing ran gradient for nucleocytoplasmic transport

Abstract

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.