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.

Unspliced XBP1 controls autophagy through FoxO1

“…FoxO1 has key functions during aging and in the regulation of autophagy in neurons [8]. In agreement with this, an accumulation of FoxO1 was observed in the brain of XBP1-deficient mice, correlating with the enhancement of autophagy [6]. However, the mechanisms linking XBP1 with the modulation of FoxO1 are not fully understood.…”

“…IRE1α signaling mediates in part the connection between the UPR and autophagy through the binding of TRAF2 to its cytosolic domain, and the activation of JNK [3,4]. Besides, XBP1 deficiency in the nervous system enhances autophagy levels, providing protection against amyotrophic lateral sclerosis [5] and Huntington's disease [6]. A recent study described a negative regulation of the transcription factor FoxO1 by XBP1s in pancreatic β cells, mediated by a physical interaction [7].…”

MIST1 Links Secretion and Stress as both Target and Regulator of the Unfolded Protein Response

“…Secretory cells and the products they manufacture are often at the center of these systems, facilitating the generation and release of response molecules ranging from digestive enzymes to antibodies and hormones. Appropriate safeguards to monitor synthesis, processing, and exocytosis in these cells are critical to human health as they prevent and mitigate multiple disease states resulting from ineffective quality control (e.g., Alzheimer's, Huntington's, and irritable bowel syndrome) or failure to execute apoptotic programs in response to stress (e.g., malignancy) (6,(63)(64)(65). These safety mechanisms are driven by response systems coupling protein stress sensors with downstream transcriptional networks.…”

“…In the case of unresolvable stress, the UPR can activate a proapoptotic program and trigger cell death, thus requiring cells to maintain tight control over the master regulators and their associated target genes. Indeed, disruption of the UPR and its corresponding response pathways has been linked to cancer progression as well as to other human diseases (4)(5)(6)(7), highlighting the need to discover new regulatory and effector UPR mechanisms that can be exploited in designing strategic biotherapeutics.…”

Genesis of ER stress in Huntington’s Disease

“…UPR induction was observed by expression of mutant Htt in yeast and mammalian cells [8,32,36,37,44]. It has also been reported in animal models of HD [36,[163][164][165]. P97 depletion by mutant Htt appears to be a major cause in the inhibition of ERAD, which causes ER stress, as p97 overexpression was sufficient for complete compensation in mammalian cells (Fig.…”