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Park, Tae-Eun
Microtissue Engineering & Nanomedicine Lab
Research Interests
  • Drug delivery, Drug development, Tissue Engineering, Organ-on-a-chip, Stem Cell Engineering, Cell Biology, 3D printing for tissue engineering, Neurobiology, Nano Biotechnology

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

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Title
LSM12-EPAC1 defines a neuroprotective pathway that sustains the nucleocytoplasmic RAN gradient
Author
Lee, JongboPark, JuminKim, Ji-hyungLee, GiwookPark, Tae-EunYoon, Ki-JunKim, Yoon KiLim, Chunghun
Issue Date
2020-12
Publisher
PUBLIC LIBRARY SCIENCE
Citation
PLOS BIOLOGY, v.18, no.12, pp.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 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.
URI
https://scholarworks.unist.ac.kr/handle/201301/48988
URL
https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001002
DOI
10.1371/journal.pbio.3001002
ISSN
1544-9173
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BIO_Journal Papers
BME_Journal Papers
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