In:
PLOS Biology, Public Library of Science (PLoS), Vol. 18, No. 12 ( 2020-12-23), p. e3001002-
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 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001002
DOI:
10.1371/journal.pbio.3001002.g001
DOI:
10.1371/journal.pbio.3001002.g002
DOI:
10.1371/journal.pbio.3001002.g003
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10.1371/journal.pbio.3001002.g004
DOI:
10.1371/journal.pbio.3001002.g005
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10.1371/journal.pbio.3001002.g006
DOI:
10.1371/journal.pbio.3001002.g007
DOI:
10.1371/journal.pbio.3001002.g008
DOI:
10.1371/journal.pbio.3001002.s001
DOI:
10.1371/journal.pbio.3001002.s002
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10.1371/journal.pbio.3001002.s003
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10.1371/journal.pbio.3001002.s004
DOI:
10.1371/journal.pbio.3001002.s005
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10.1371/journal.pbio.3001002.s006
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10.1371/journal.pbio.3001002.s007
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10.1371/journal.pbio.3001002.s008
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10.1371/journal.pbio.3001002.s009
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10.1371/journal.pbio.3001002.s010
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10.1371/journal.pbio.3001002.s011
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10.1371/journal.pbio.3001002.s012
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10.1371/journal.pbio.3001002.s013
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10.1371/journal.pbio.3001002.s014
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10.1371/journal.pbio.3001002.s015
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10.1371/journal.pbio.3001002.s016
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10.1371/journal.pbio.3001002.s017
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10.1371/journal.pbio.3001002.s018
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10.1371/journal.pbio.3001002.s019
DOI:
10.1371/journal.pbio.3001002.s020
DOI:
10.1371/journal.pbio.3001002.s021
DOI:
10.1371/journal.pbio.3001002.r001
DOI:
10.1371/journal.pbio.3001002.r002
DOI:
10.1371/journal.pbio.3001002.r003
DOI:
10.1371/journal.pbio.3001002.r004
DOI:
10.1371/journal.pbio.3001002.r005
DOI:
10.1371/journal.pbio.3001002.r006
DOI:
10.1371/journal.pbio.3001002.r007
DOI:
10.1371/journal.pbio.3001002.r008
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2020
detail.hit.zdb_id:
2126773-X
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