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

Jongbo Lee; Jumin Park; Ji-Hyung Kim; Giwook Lee; Tae-Eun Park; Ki-Jun Yoon; Yoon Ki Kim; Chunghun Lim

doi:10.1371/journal.pbio.3001002

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

PLoS Biol. 2020 Dec 23;18(12):e3001002. doi: 10.1371/journal.pbio.3001002. eCollection 2020 Dec.

Authors

Jongbo Lee¹, Jumin Park¹, Ji-Hyung Kim¹, Giwook Lee¹, Tae-Eun Park¹, Ki-Jun Yoon², Yoon Ki Kim^{3

4}, Chunghun Lim¹

Affiliations

¹ School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea.
² Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
³ Creative Research Initiatives Center for Molecular Biology of Translation, Korea University, Seoul, Republic of Korea.
⁴ Division of Life Sciences, Korea University, Seoul, Republic of Korea.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus
Amyotrophic Lateral Sclerosis / genetics
Amyotrophic Lateral Sclerosis / metabolism
Amyotrophic Lateral Sclerosis / pathology
C9orf72 Protein / genetics
C9orf72 Protein / metabolism
Cell Nucleus / metabolism
Circadian Rhythm Signaling Peptides and Proteins / genetics
Circadian Rhythm Signaling Peptides and Proteins / metabolism*
Cyclic AMP / metabolism
Cytoplasm / metabolism
Frontotemporal Dementia / genetics
Frontotemporal Dementia / metabolism
Frontotemporal Dementia / pathology
Guanine Nucleotide Exchange Factors / genetics
Guanine Nucleotide Exchange Factors / metabolism*
Humans
Induced Pluripotent Stem Cells / metabolism
Neurons / metabolism
Neurons / pathology
Nuclear Pore / metabolism
Nucleocytoplasmic Transport Proteins / genetics
Nucleocytoplasmic Transport Proteins / metabolism*
ran GTP-Binding Protein / metabolism*

Substances

C9orf72 Protein
C9orf72 protein, human
Circadian Rhythm Signaling Peptides and Proteins
Guanine Nucleotide Exchange Factors
Nucleocytoplasmic Transport Proteins
RAN protein, human
RAPGEF3 protein, human
Cyclic AMP
ran GTP-Binding Protein

Grants and funding

This work was supported by grants from the Suh Kyungbae Foundation (SUHF-17020101[CL]); from the National Research Foundation funded by the Ministry of Science and Information & Communication Technology (MSIT), Republic of Korea (NRF-2018R1A2B2004641[CL]; NRF-2018R1A5A1024261[KJY, YKK, and CL]); and from the Korea Health Technology R&D Project through the KHIDI funded by the Ministry of Health & Welfare, Republic of Korea (HI16C1747[CL]). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.