< i > LSM12 < /i > - < i > EPAC1 < /i > defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient

by Jongbo Lee, Jumin Park, Ji-hyung Kim, Giwook Lee, Tae-Eun Park, Ki-Jun Yoon, Yoon Ki Kim, Chunghun Lim Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such asC9ORF72-associated amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we identify a neuroprotective pathway of like-Sm protein 12 (LSM12) and exchange protein directly activated by cyclic AMP 1 (EPAC1) that sustains the nucleocytoplasmic RAN gradient and thereby suppresses NCT dysfunction by theC9ORF72-derived poly(glycine-arginine) protein. LSM12 depletion in human neuroblastoma cells aggravated poly(GR)-induced impairment of NCT and nuclear integrity while promoting the nuclear accumulation of poly(GR) granules. In fact,LSM12 posttranscriptionally up-regulatedEPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects inLSM12-deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression ofLSM12 andEPAC1. Lentiviral overexpression of LSM12 or EPAC1 indeed restored the RAN gradient, mitigated the pathogenic mislocalization of TDP-43, and suppressed caspase-3 activation for apoptosis in C9-ALS iPSNs. EPAC1 depletion biochemically dissociated RAN-importin β1 from the cytoplasmic nuclear pore complex, thereby dissipating the nucleocytoplasmic RAN gradient essential for NCT. These findings define theLSM12-EPAC1 pathway as an important suppressor of...
Source: PLoS Biology: Archived Table of Contents - Category: Biology Authors: Source Type: research