XBP-1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy

hetz C.; Thielen P; Matus, S; Nassif, M; Court, F; Kiffin, R; Martinez, G; Cuervo, AM; Brown, RH; Glimcher, LH

Keywords: transgenic mice, disease, up-regulation, neurodegeneration, endoplasmic-reticulum stress, amyotrophic lateral sclerosis, als, autophagy, endoplasmic reticulum stress, unfolded protein response, er stress, transcription factor xbp-1, motor-neurons, xbp-1, mutant superoxide-dismutase


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. © 2009 by Cold Spring Harbor Laboratory Press.

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Título según WOS: XBP-1 deficiency in the nervous system reveals a homeostatic switch to activate autophagy
Título según SCOPUS: XBP-1 deficiency in the nervous system protects against amyotrophic lateral sclerosis by increasing autophagy
Título de la Revista: AUTOPHAGY
Volumen: 5
Número: 8
Fecha de publicación: 2009
Página de inicio: 1226
Página final: 1228
Idioma: English
URL: http://genesdev.cshlp.org/cgi/doi/10.1101/gad.1830709