Research Around the World: Chile

Alleviating Secretory Pathway Stress in Huntington Disease

By: Rene Vidal, PhD and Claudio Hetz, PhD

chileMany clinical trials that use drugs validated in mouse models of HD have failed to alleviate disease progression in humans. Preclinical studies have been performed in transgenic mice of pure genetic backgrounds that overexpress high levels of truncated forms of mutant huntingtin (mHtt). This mouse model, and other HD mouse models, does not truly replicate HD in humans. Several HD mouse models are available, including many mHtt knock-in mice. However, these mouse models often require the use of homozygous mHtt alleles, because mice carrying only one mutant allele develop very minor phenotypes and fail to express most of the distinctive features of HD. Also, cellular processes known to be important for neuronal function are often altered in HD mouse models. Researchers are developing strategies to identify molecular events that transcend various HD cellular and animal models, and correlate these with alterations observed in human HD-derived samples.

A common molecular feature described in cellular and animal models of HD is the occurrence of protein folding stress responses in the brain, possibly caused by alterations of the protein secretory pathway. Defects in virtually every step of the secretory pathway are observed in HD neurons, such as perturbations in protein folding networks; vesicular transport; the endoplasmic reticulum (ER) and Golgi 3D patterning; protein quality control mechanisms (i.e. autophagy and the ER-associated degradation pathway); and ER calcium homeostasis. Many alterations of the of the protein secretory pathway generate alterations in the protein folding process and lead to a pathological condition known as ER stress.

Some investigators take a global view of mHtt pathogenesis and hypothesize that strategies aimed at alleviating secretory pathway stress may have beneficial effects in HD. Studies have documented activation of the unfolded protein response (UPR), an adaptive reaction against ER stress, in animal models of HD and human postmortem samples from HD patients. Studies in HD cellular models support the concept that chronic ER stress contributes to HD related neurodegeneration1. Lee and colleagues demonstrated that the ER stress sensor IRE1 may govern mHtt aggregation and neurotoxicity through a molecular crosstalk with autophagy, another homeostatic pathway2. IRE1 enhanced mHtt degradation by the lysosome-autophagy pathway. Targeting the stress networks involved in protein homeostasis is an interesting method of disease intervention. We investigated the possible contribution of ER stress to phenotypic HD in vivo using a recently generated strain of mice that selectively lack XBP1 in neurons (the downstream target of IRE1).

Despite predictions that XBP1 deficiency would increase the severity of experimental HD, we observed that this genetic manipulation triggered resistance to development of the disease. XBP1 deficiency enhanced neuronal survival and improved motor performance of a full-length mHtt transgenic mouse (the YAC128 model)3. We also validated the effects of XBP1 on mHtt levels in a heterozygous knock-in mouse HD model. The mechanism of protection appears to be related to the upregulation of autophagy and the degradation of full-length mHtt in the lysosomes. In collaboration with Dr. Ana Maria Cuervo (Albert Einstein College of Medicine), we showed that mHtt is delivered to autophagosomes and autophagolysosomes in vivo upon targeting XBP1 in the nervous system. This observation suggests that a homeostatic crosstalk between the UPR and autophagy is a response against mHtt pathogenesis that may be manipulated to provide protection against HD. At the molecular level, we found a negative regulation of the transcription factor FoxO1 by XBP1 in vivo. Fox01 is a major protein involved in ageing and operates as a macrostress integrator of metabolic and stress processes.

Secretory pathway stress in HD could be manipulated by targeting different components of this network, including homeostatic pathways such as the UPR and autophagy.

General pharmacological strategies may include administration of chemical chaperones such as TUDCA or 4-PBA, modulators of UPR components (i.e. available IRE1 inhibitors), or autophagy enhancers such as trehalose or rapamycin. The use of gene therapy to target proteinfolding stress has been applied to other neurodegenerative diseases with the aim of targeting protein homeostasis, and may be an approach to consider, since HD is a disease that progresses slowly.

The development of network modifying therapeutic interventions may lead to important protective advances in the HD field. Minor shifts in the protein homeostasis network may involve the alteration of hundreds of target genes that as a whole may result in beneficial effects in HD. Thus, modulating global homeostatic processes could have broad impact for chronic alterations observed in HD that involve multiple aspects of neuronal physiology and protein homeostasis.


1 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 Feb; 11(1):1-12.

2 Lee H, Noh JY, Oh Y, et al. IRE1 plays an essential role in ER stress-mediated aggregation of mutant huntingtin via the inhibition of autophagy flux. Hum Mol Genet 2012 Jan; 21(1): 101-14.

3 Vidal RL, Figueroa A, Court FA, et al. Targeting the UPR transcription factor XBP1 protects against Huntington’s disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 2012 May; 21(10):2245-62.