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

Jongbo Lee,Giwook Lee,Chunghun Lim,Jumin Park,Ji-Hyung Kim,Yoon Ki Kim,Tae-Eun Park,Ki-Jun Yoon,Gillian P Bates

doi:10.1371/journal.pbio.3001002

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.

Highlights

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that manifests as progressive loss of motor neurons, paralysis, and respiratory failure [1]
Given that stress granule (SG) assembly is suppressed by loss of ATXN2 function [43,45,46], we asked if ATXN2-associated like-Sm protein 12 (LSM12) plays a similar role in SG formation
Whereas LSM12 may stabilize ATXN2 through the formation of a protein complex, we found that ATXN2 overexpression partially rescued the average number and size of arseniteinduced SGs in LSM12-depleted cells (Fig 1D and 1E)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that manifests as progressive loss of motor neurons, paralysis, and respiratory failure [1]. ALS shares pathological hallmarks with frontotemporal dementia (FTD), a clinically distinct neurodegenerative disorder accompanied by behavioral changes and language difficulties [2,3]. Familial ALS/FTD is most commonly caused by the pathogenic expansion of GGGGCC hexanucleotide repeats in the C9ORF72 locus [4,5,6]. Additional genetic factors associated with ALS/FTD include TDP-. Sequencing experiments can be downloaded from GEO (accession number GSE160159)

Methods

Results

Conclusion