XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy.
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.
Hetz
Claudio
C
Institute 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
Thielen
Peter
P
Matus
Soledad
S
Nassif
Melissa
M
Court
Felipe
F
Kiffin
Roberta
R
Martinez
Gabriela
G
Cuervo
Ana María
AM
Brown
Robert H
RH
Glimcher
Laurie H
LH
D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D004722:Endoribonucleases / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008136:Longevity / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009420:Nervous System / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D013116:Spinal Cord; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; C000606290:SOD1 protein, human; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases