Format

Send to:

Choose Destination
See comment in PubMed Commons below
Hum Mol Genet. 2009 Jul 15;18(14):2622-31. doi: 10.1093/hmg/ddp196. Epub 2009 Apr 29.

Deletions and missense mutations of EPM2A exacerbate unfolded protein response and apoptosis of neuronal cells induced by endoplasm reticulum stress.

Author information

  • 1Division of Immunotherapy, Section of General Surgery, Department of Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Abstract

The majority of the Lafora's disease (LD) is caused by defect in the EPM2A gene, including missense and nonsense mutations and deletions. These defects mainly occur in the carbohydrate-binding domain, and how these mutations cause neuronal defects is under active investigation. Here, we report that the mutant proteins encoded by all missense mutations and most deletions tested are unstable, insoluble and ubiquitinated, and are accumulated in aggresome-like structures. The effect of apparent 'gain-of-function' mutations can be corrected by co-transfection of wild-type EPM2A cDNA, which is consistent with the recessive nature of these mutations in LD patients. In a neuronal cell line, these mutant aggregates exacerbate endoplasm reticulum (ER) stress and make the cells susceptible to the apoptosis induced by ER stressor, thapsigargin. The chemical chaperon, 4-phenylbutyrate, increased the mutant solubility, reduced the ER stress and dulled the sensitivity of mutant neuronal cells to apoptosis induced by thapsigargin and the mutant laforin proteins. The increased sensitivity to ER stress-induced apoptosis may contribute to LD pathogenesis.

PMID:
19403557
[PubMed - indexed for MEDLINE]
PMCID:
PMC2701334
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for HighWire Icon for PubMed Central
    Loading ...
    Write to the Help Desk