LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Lee, Jongbo | - |
dc.contributor.author | Park, Jumin | - |
dc.contributor.author | Kim, Ji-hyung | - |
dc.contributor.author | Lee, Giwook | - |
dc.contributor.author | Park, Tae-Eun | - |
dc.contributor.author | Yoon, Ki-Jun | - |
dc.contributor.author | Kim, Yoon Ki | - |
dc.contributor.author | Lim, Chunghun | - |
dc.date.accessioned | 2021-08-30T06:37:22Z | - |
dc.date.available | 2021-08-30T06:37:22Z | - |
dc.date.created | 2021-06-19 | - |
dc.date.issued | 2020-12 | - |
dc.identifier.issn | 1544-9173 | - |
dc.identifier.uri | https://scholar.korea.ac.kr/handle/2021.sw.korea/51228 | - |
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.language.iso | en | - |
dc.publisher | PUBLIC LIBRARY SCIENCE | - |
dc.subject | AMYOTROPHIC-LATERAL-SCLEROSIS | - |
dc.subject | FRONTOTEMPORAL LOBAR DEGENERATION | - |
dc.subject | STRESS GRANULE FORMATION | - |
dc.subject | NUCLEAR-PORE COMPLEXES | - |
dc.subject | REPEAT EXPANSION | - |
dc.subject | PROTEIN IMPORT | - |
dc.subject | HEXANUCLEOTIDE REPEAT | - |
dc.subject | C9ORF72 EXPANSION | - |
dc.subject | TRANSPORT DEFECTS | - |
dc.subject | ANALYSES IDENTIFY | - |
dc.title | LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient | - |
dc.type | Article | - |
dc.contributor.affiliatedAuthor | Kim, Yoon Ki | - |
dc.identifier.doi | 10.1371/journal.pbio.3001002 | - |
dc.identifier.scopusid | 2-s2.0-85098938120 | - |
dc.identifier.wosid | 000603070600002 | - |
dc.identifier.bibliographicCitation | PLOS BIOLOGY, v.18, no.12 | - |
dc.relation.isPartOf | PLOS BIOLOGY | - |
dc.citation.title | PLOS BIOLOGY | - |
dc.citation.volume | 18 | - |
dc.citation.number | 12 | - |
dc.type.rims | ART | - |
dc.type.docType | Article | - |
dc.description.journalClass | 1 | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
dc.relation.journalResearchArea | Biochemistry & Molecular Biology | - |
dc.relation.journalResearchArea | Life Sciences & Biomedicine - Other Topics | - |
dc.relation.journalWebOfScienceCategory | Biochemistry & Molecular Biology | - |
dc.relation.journalWebOfScienceCategory | Biology | - |
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 | - |
Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.
(02841) 서울특별시 성북구 안암로 14502-3290-1114
COPYRIGHT © 2021 Korea University. All Rights Reserved.
Certain data included herein are derived from the © Web of Science of Clarivate Analytics. All rights reserved.
You may not copy or re-distribute this material in whole or in part without the prior written consent of Clarivate Analytics.