DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Jongbo | ko |
dc.contributor.author | Park, Jumin | ko |
dc.contributor.author | Kim, Ji-hyung | ko |
dc.contributor.author | Lee, Giwook | ko |
dc.contributor.author | Park, Tae-Eun | ko |
dc.contributor.author | Yoon, Ki-Jun | ko |
dc.contributor.author | Kim, Yoon Ki | ko |
dc.contributor.author | Lim, Chunghun | ko |
dc.date.accessioned | 2021-01-28T05:53:52Z | - |
dc.date.available | 2021-01-28T05:53:52Z | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.created | 2021-01-19 | - |
dc.date.issued | 2020-12 | - |
dc.identifier.citation | PLOS BIOLOGY, v.18, no.12 | - |
dc.identifier.issn | 1544-9173 | - |
dc.identifier.uri | http://hdl.handle.net/10203/280045 | - |
dc.description.abstract | 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 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.language | English | - |
dc.publisher | PUBLIC LIBRARY SCIENCE | - |
dc.title | LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient | - |
dc.type | Article | - |
dc.identifier.wosid | 000603070600002 | - |
dc.identifier.scopusid | 2-s2.0-85098938120 | - |
dc.type.rims | ART | - |
dc.citation.volume | 18 | - |
dc.citation.issue | 12 | - |
dc.citation.publicationname | PLOS BIOLOGY | - |
dc.identifier.doi | 10.1371/journal.pbio.3001002 | - |
dc.contributor.localauthor | Yoon, Ki-Jun | - |
dc.contributor.localauthor | Kim, Yoon Ki | - |
dc.contributor.localauthor | Lim, Chunghun | - |
dc.contributor.nonIdAuthor | Lee, Jongbo | - |
dc.contributor.nonIdAuthor | Park, Jumin | - |
dc.contributor.nonIdAuthor | Kim, Ji-hyung | - |
dc.contributor.nonIdAuthor | Lee, Giwook | - |
dc.contributor.nonIdAuthor | Park, Tae-Eun | - |
dc.description.isOpenAccess | Y | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordPlus | AMYOTROPHIC-LATERAL-SCLEROSIS | - |
dc.subject.keywordPlus | FRONTOTEMPORAL LOBAR DEGENERATION | - |
dc.subject.keywordPlus | STRESS GRANULE FORMATION | - |
dc.subject.keywordPlus | NUCLEAR-PORE COMPLEXES | - |
dc.subject.keywordPlus | REPEAT EXPANSION | - |
dc.subject.keywordPlus | PROTEIN IMPORT | - |
dc.subject.keywordPlus | HEXANUCLEOTIDE REPEAT | - |
dc.subject.keywordPlus | C9ORF72 EXPANSION | - |
dc.subject.keywordPlus | TRANSPORT DEFECTS | - |
dc.subject.keywordPlus | ANALYSES IDENTIFY | - |
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