Open AccessLSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient
Author(s) -
Jongbo Lee,
Jumin Park,
Ji Hyung Kim,
Giwook Lee,
TaeEun Park,
Ki Jun Yoon,
Yoon Ki Kim,
Chunghun Lim
Publication year - 2020
Publication title -
plos biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.127
H-Index - 271
eISSN - 1545-7885
pISSN - 1544-9173
DOI - 10.1371/journal.pbio.3001002
Subject(s) - ran , c9orf72 , importin , microbiology and biotechnology , biology , nuclear transport , nuclear export signal , amyotrophic lateral sclerosis , cytoplasm , cell nucleus , biochemistry , trinucleotide repeat expansion , medicine , allele , disease , pathology , gene
Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as C9ORF72 -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 the C9ORF72 -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-regulated EPAC1 expression, whereas EPAC1 overexpression rescued the RAN gradient and NCT defects in LSM12 -deleted cells. C9-ALS patient-derived neurons differentiated from induced pluripotent stem cells (C9-ALS iPSNs) displayed low expression of LSM12 and EPAC1 . 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 the LSM12 - EPAC1 pathway as an important suppressor of the NCT-related pathologies in C9-ALS/FTD.