LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient

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dc.contributor.authorLee, Jongboko
dc.contributor.authorPark, Juminko
dc.contributor.authorKim, Ji-hyungko
dc.contributor.authorLee, Giwookko
dc.contributor.authorPark, Tae-Eunko
dc.contributor.authorYoon, Ki-Junko
dc.contributor.authorKim, Yoon Kiko
dc.contributor.authorLim, Chunghunko
dc.date.accessioned2021-01-28T05:53:52Z-
dc.date.available2021-01-28T05:53:52Z-
dc.date.created2021-01-19-
dc.date.created2021-01-19-
dc.date.created2021-01-19-
dc.date.issued2020-12-
dc.identifier.citationPLOS BIOLOGY, v.18, no.12-
dc.identifier.issn1544-9173-
dc.identifier.urihttp://hdl.handle.net/10203/280045-
dc.description.abstractNucleocytoplasmic 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 beta 1 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.-
dc.languageEnglish-
dc.publisherPUBLIC LIBRARY SCIENCE-
dc.titleLSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient-
dc.typeArticle-
dc.identifier.wosid000603070600002-
dc.identifier.scopusid2-s2.0-85098938120-
dc.type.rimsART-
dc.citation.volume18-
dc.citation.issue12-
dc.citation.publicationnamePLOS BIOLOGY-
dc.identifier.doi10.1371/journal.pbio.3001002-
dc.contributor.localauthorYoon, Ki-Jun-
dc.contributor.localauthorKim, Yoon Ki-
dc.contributor.nonIdAuthorLee, Jongbo-
dc.contributor.nonIdAuthorPark, Jumin-
dc.contributor.nonIdAuthorKim, Ji-hyung-
dc.contributor.nonIdAuthorLee, Giwook-
dc.contributor.nonIdAuthorPark, Tae-Eun-
dc.contributor.nonIdAuthorLim, Chunghun-
dc.description.isOpenAccessY-
dc.type.journalArticleArticle-
dc.subject.keywordPlusAMYOTROPHIC-LATERAL-SCLEROSIS-
dc.subject.keywordPlusFRONTOTEMPORAL LOBAR DEGENERATION-
dc.subject.keywordPlusSTRESS GRANULE FORMATION-
dc.subject.keywordPlusNUCLEAR-PORE COMPLEXES-
dc.subject.keywordPlusREPEAT EXPANSION-
dc.subject.keywordPlusPROTEIN IMPORT-
dc.subject.keywordPlusHEXANUCLEOTIDE REPEAT-
dc.subject.keywordPlusC9ORF72 EXPANSION-
dc.subject.keywordPlusTRANSPORT DEFECTS-
dc.subject.keywordPlusANALYSES IDENTIFY-
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