Format

Send to:

Choose Destination
See comment in PubMed Commons below
Genes Dev. 2009 Oct 1;23(19):2294-306. doi: 10.1101/gad.1830709. Epub 2009 Sep 17.

XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.

Author information

  • 1Institute of Biomedical Sciences, The FONDAP Center for Molecular Studies of the Cell (CEMC) and the Millennium Nucleus for Neural Morphogenesis (NEMO), University of Chile, Santiago, Chile. chetz@med.uchile.cl

Abstract

Mutations in superoxide dismutase-1 (SOD1) cause familial amyotrophic lateral sclerosis (fALS). Recent evidence implicates adaptive responses to endoplasmic reticulum (ER) stress in the disease process via a pathway known as the unfolded protein response (UPR). Here, we investigated the contribution to fALS of X-box-binding protein-1 (XBP-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control. Despite expectations that XBP-1 deficiency would enhance the pathogenesis of mutant SOD1, we observed a dramatic decrease in its toxicity due to an enhanced clearance of mutant SOD1 aggregates by macroautophagy, a cellular pathway involved in lysosome-mediated protein degradation. To validate these observations in vivo, we generated mutant SOD1 transgenic mice with specific deletion of XBP-1 in the nervous system. XBP-1-deficient mice were more resistant to developing disease, correlating with increased levels of autophagy in motoneurons and reduced accumulation of mutant SOD1 aggregates in the spinal cord. Post-mortem spinal cord samples from patients with sporadic ALS and fALS displayed a marked activation of both the UPR and autophagy. Our results reveal a new function of XBP-1 in the control of autophagy and indicate critical cross-talk between these two signaling pathways that can provide protection against neurodegeneration.

PMID:
19762508
[PubMed - indexed for MEDLINE]
PMCID:
PMC2758741
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