Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy
- PMID: 22337954
- PMCID: PMC3335312
- DOI: 10.1093/hmg/dds040
Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy
Abstract
Mutations leading to expansion of a poly-glutamine track in Huntingtin (Htt) cause Huntington's disease (HD). Signs of endoplasmic reticulum (ER) stress have been recently reported in animal models of HD, associated with the activation of the unfolded protein response (UPR). Here we have investigated the functional contribution of ER stress to HD by targeting the expression of two main UPR transcription factors, XBP1 and ATF4 (activating transcription factor 4), in full-length mutant Huntingtin (mHtt) transgenic mice. XBP1-deficient mice were more resistant to developing disease features, associated with improved neuronal survival and motor performance, and a drastic decrease in mHtt levels. The protective effects of XBP1 deficiency were associated with enhanced macroautophagy in both cellular and animal models of HD. In contrast, ATF4 deficiency did not alter mHtt levels. Although, XBP1 mRNA splicing was observed in the striatum of HD transgenic brains, no changes in the levels of classical ER stress markers were detected in symptomatic animals. At the mechanistic level, we observed that XBP1 deficiency led to augmented expression of Forkhead box O1 (FoxO1), a key transcription factor regulating autophagy in neurons. In agreement with this finding, ectopic expression of FoxO1 enhanced autophagy and mHtt clearance in vitro. Our results provide strong evidence supporting an involvement of XBP1 in HD pathogenesis probably due to an ER stress-independent mechanism involving the control of FoxO1 and autophagy levels.
Figures








References
-
- Matus S., Glimcher L., Hetz C. Protein folding stress in neurodegenerative diseases: a glimpse into the ER. Curr. Opin. Cell Biol. 2011;23:239–252. doi:10.1016/j.ceb.2011.01.003. - DOI - PubMed
-
- Bossy-Wetzel E., Petrilli A., Knott A.B. Mutant huntingtin and mitochondrial dysfunction. Trends Neurosci. 2008;31:609–616. doi:10.1016/j.tins.2008.09.004. - DOI - PMC - PubMed
-
- Vidal R., Caballero B., Couve A., Hetz C. Converging pathways in the occurrence of endoplasmic reticulum (ER) stress in Huntington's disease. Curr. Mol. Med. 2011;11:1–12. doi:10.2174/156652411794474419. - DOI - PubMed
-
- Rubinsztein D.C. Lessons from animal models of Huntington's disease. Trends Genet. 2002;18:202–209. doi:10.1016/S0168-9525(01)02625-7. - DOI - PubMed
-
- Williams A.J., Paulson H.L. Polyglutamine neurodegeneration: protein misfolding revisited. Trends Neurosci. 2008;31:521–528. doi:10.1016/j.tins.2008.07.004. - DOI - PMC - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Molecular Biology Databases
Research Materials
Miscellaneous