dc.citation.conferencePlace |
US |
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dc.citation.title |
Neuroscience 2019 |
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dc.contributor.author |
Lee, Jongbo |
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dc.contributor.author |
Park, Jumin |
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dc.contributor.author |
Kim, Ji-hyung |
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dc.contributor.author |
Lim, Chunghun |
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dc.date.accessioned |
2024-01-31T23:37:30Z |
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dc.date.available |
2024-01-31T23:37:30Z |
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dc.date.created |
2019-10-30 |
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dc.date.issued |
2019-10-19 |
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dc.description.abstract |
Nucleocytoplasmic transport (NCT) defects have been implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) associated with C9orf72 mutations. Here we identify a neuroprotective pathway of like-Sm protein 12 (Lsm12) and Exchange protein directly activated by cyclic AMP (Epac1) that suppresses NCT dysfunction by C9orf72-derived poly(glycine-arginine) proteins. Loss of Lsm12 function exacerbated neurodegeneration in Drosophila models of the poly(GR)-induced ALS/FTD. Consistently, Lsm12 depletion in human neuroblastoma cells enhanced the poly(GR)-induced impairment of NCT while promoting the formation of nuclear poly(GR) granules. Overexpression of ALS-associated Lsm12 mutant comparably strengthened the poly(GR) toxicity, indicating dominant-negative effects. Transcriptome analyses further revealed that Lsm12 up-regulates Epac1 expression whereas Epac1 overexpression rescued NCT defects in Lsm12-deleted cells. In fact, Epac1 depletion dissociated Ran/Importin β1 from cytoplasmic nucleopore complex, thereby dampening Ran gradient. These findings unveil a conserved role of the Lsm12-Epac1 pathway in the NCT-relevant pathogenesis of C9orf72-dependent ALS/FTD. |
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dc.identifier.bibliographicCitation |
Neuroscience 2019 |
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dc.identifier.uri |
https://scholarworks.unist.ac.kr/handle/201301/79078 |
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dc.identifier.url |
https://www.abstractsonline.com/pp8/#!/7883/presentation/44084 |
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dc.publisher |
Society for Neuroscience |
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dc.title |
Lsm12-Epac1 pathway suppresses C9orf72 poly(GR)-induced neurodegeneration by establishing ran gradient for nucleocytoplasmic transport |
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dc.type |
Conference Paper |
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dc.date.conferenceDate |
2019-10-19 |
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