Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy
Authors: Peter Thielen
Rene L Vidal
Juan Segura-Aguilar
Felipe A Court
Benjamin Caballero
Ana Maria Cuervo
Laurie H Glimcher
Alicia Figueroa
Craig Wirth
Roberta Kiffin
Claudio Hetz
Claudia Molina
Journal: Human Molecular Genetics (2012)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Huntington's disease; endoplasmic reticulum stress; unfolded protein response; XBP1; ATF4
Affiliations: Faculty of Medicine, Neuroscience Biomedical Institute, University of Chile, Santiago, Chile.

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. 

Retracted: No

PubPeer comments:
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 #1 This is the first time I have heard anything about this. No mention was made to me by Dr. Hetz about this nor did anyone directly contact me about this. , 
 #5 Thank you for your reply. Unfortunately, not all PubPeer commenters input author email addresses, so perhaps that is why you were not notified. , 
 Supplementary Fig. 4: If you get the supplemental file from NCBI and copy the Hsp90 band to paint, you get this: ![file] These bands differ from the raw data provided by the authors in their website (page 2: https: www.hetzlab.cl wp-content uploads 2017 06 Data-backup-and-LAB-actions-from-comments-Pubpeer-2_compressed.pdf) ![file] , 
 We apologize for the initial mistake but this error was corrected in the year 2012 . The problem was generated by the presence of two versions of the supplementary figure 4A still available online in different platforms. In the old version of this figure, in panels A and D we tested the efficiency of shRNA knockdown in stable cell lines for the genes XBP1, ATF4, and control and then monitored ATF4 and XBP1 expression by Western blot. These 3 cell lines were generated at the same time and thus used the same control shRNA in most experiments. This is why in both panels A and D the control image (shCTR) were the same (from the same blot), repeated twice in both panels figure (Figure 1A). We apologize for this mistake since it was not mentioned in the figure legend. As soon as we noticed this error we contacted the editor and send the original data to take action and performed an online correction of the supplementary figure 4 including a new experiment (Figure 1B). They decided to replace the supplementary material for a new one without any correction since there was no error in the figure, just that it was not properly mentioned the splice (see exchange of emails during 2012 at https: www.hetzlab.cl data ). This case was considered closed in 2012 by HMG and no further actions needed. Unfortunately, we noticed an additional error when selecting the Hsp90 bands for loading control of the supplementary figure 4A, because the selection of the bands was displaced by mistake including the next lane (Figure 2A). For full transparency, here we provide the full scans of the online and corrected supplementary figure 4 (Figure 2). Importantly, the biological conclusion of the experiment is not altered by this mistake. We will contact the editorial office of Human Molecular Genetics to replace supplementary figure 4 with the corrected version of the figure if necessary. ![file] **Figure 1. Side-by-side comparison of both online versions.** (A) Original version of the supplementary figure 4 containing the image duplication as explained in the text. (B) Corrected supplementary figure 4 available online in the HMG site. ![file] **Figure 2. Raw data presentation.** (A) Raw data of the corrected supplementary figure 4A. (B) Raw data of the corrected supplementary figure 4D. Both figures are available online at the HMG site. , 
 https: www.uchile.cl noticias 179784 comunicado-sobre-profesor-hetz ,