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

Claudio Hetz, Peter Thielen, Soledad Matus, Melissa Nassif, Felipe Court, Roberta Kiffin, Gabriela Martinez, Ana María Cuervo, Robert H. Brown, Laurie H. Glimcher

Research output: Contribution to journalArticle

368 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2294-2306
Number of pages13
JournalGenes and Development
Volume23
Issue number19
DOIs
StatePublished - Oct 1 2009

Keywords

  • Amyotrophic lateral sclerosis
  • Autophagy
  • Endoplasmic reticulum stress
  • Unfolded protein response
  • XBP-1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Hetz, C., Thielen, P., Matus, S., Nassif, M., Court, F., Kiffin, R., Martinez, G., Cuervo, A. M., Brown, R. H., & Glimcher, L. H. (2009). XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy. Genes and Development, 23(19), 2294-2306. https://doi.org/10.1101/gad.1830709