XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy
- Claudio Hetz1,2,8,
- Peter Thielen2,
- Soledad Matus1,
- Melissa Nassif1,
- Felipe Court3,
- Roberta Kiffin4,
- Gabriela Martinez1,
- Ana María Cuervo4,
- Robert H. Brown5 and
- Laurie H. Glimcher2,6,7
- 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;
- 2Department of Immunology and Infectious diseases, Harvard School of Public Health, Boston Massachusetts 02115, USA;
- 3Department of Physiology, Faculty of Biological Science, Pontifical Catholic University of Chile, Santiago, Chile;
- 4Institute for Aging Studies, Albert Einstein College of Medicine, Bronx, New York 10461,USA;
- 5MassGeneral Institute for Neurodegenerative Disease, Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA;
- 6Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA
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.
Keywords
- Amyotrophic lateral sclerosis
- unfolded protein response
- endoplasmic reticulum stress
- XBP-1
- autophagy
Footnotes
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↵7 Corresponding authors.
E-MAIL lglimche{at}hsph.harvard.edu; FAX (617) 432-0084.
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↵8 E-MAIL chetz{at}med.uchile.cl; FAX 56-2-978-6871.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.1830709.
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Supplemental material is available at http://www.genesdev.org.
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- Received June 10, 2009.
- Accepted August 19, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press