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

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 acti...

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Bibliographic Details
Published in:PLoS biology 2020-12, Vol.18 (12), p.e3001002-e3001002
Main Authors: Lee, Jongbo, Park, Jumin, Kim, Ji-Hyung, Lee, Giwook, Park, Tae-Eun, Yoon, Ki-Jun, Kim, Yoon Ki, Lim, Chunghun
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Amyotrophic Lateral Sclerosis - metabolism
Amyotrophic Lateral Sclerosis - pathology
Assembly
Biological clocks
Biology and Life Sciences
C9orf72 Protein - genetics
C9orf72 Protein - metabolism
Cell culture
Cell Nucleus - metabolism
Circadian rhythm
Circadian Rhythm Signaling Peptides and Proteins - genetics
Circadian Rhythm Signaling Peptides and Proteins - metabolism
Circadian rhythms
Clock gene
Cyclic AMP - metabolism
Cytoplasm - metabolism
Cytotoxicity
Depletion
Drosophila
Frontotemporal dementia
Frontotemporal Dementia - genetics
Frontotemporal Dementia - metabolism
Frontotemporal Dementia - pathology
Fruit flies
Guanine Nucleotide Exchange Factors - genetics
Guanine Nucleotide Exchange Factors - metabolism
Humans
Inclusions
Induced Pluripotent Stem Cells - metabolism
Insects
Mutation
Neurodegeneration
Neurons - metabolism
Neurons - pathology
Neuroprotection
Nuclear Pore - metabolism
Nucleocytoplasmic Transport Proteins - genetics
Nucleocytoplasmic Transport Proteins - metabolism
Oxidative stress
Pathogenesis
Periodicity
Phenotypes
Physical Sciences
Polyglutamine
Proteins
ran GTP-Binding Protein - metabolism
Research and Analysis Methods
RNA polymerase
Translation
Variance analysis
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Summary: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.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3001002