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Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease
José R. Naranjo, … , Jia-Yi Li, Britt Mellström
José R. Naranjo, … , Jia-Yi Li, Britt Mellström
Published January 11, 2016
Citation Information: J Clin Invest. 2016;126(2):627-638. https://doi.org/10.1172/JCI82670.
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Research Article Neuroscience Article has an altmetric score of 22

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

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Abstract

Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD.

Authors

José R. Naranjo, Hongyu Zhang, Diego Villar, Paz González, Xose M. Dopazo, Javier Morón-Oset, Elena Higueras, Juan C. Oliveros, María D. Arrabal, Angela Prieto, Pilar Cercós, Teresa González, Alicia De la Cruz, Juan Casado-Vela, Alberto Rábano, Carmen Valenzuela, Marta Gutierrez-Rodriguez, Jia-Yi Li, Britt Mellström

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Figure 6

Repaglinide activates ATF6 processing in mouse striatal neurons.

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Repaglinide activates ATF6 processing in mouse striatal neurons.
(A) Wes...
(A) Western blot analysis of whole-cell extracts from STHdhQ7/7 cells stimulated with tunicamycin (200 ng/ml) and repaglinide (100 nM) alone or in combination. Migration of full-length ATF6 (Fl-ATF6) and the N-terminal ATF6 (Nt-ATF6) are shown. Asterisk marks a nonspecific band. Loading control with nonphosphorylated ERK is shown below. The relative ratio of Nt-ATF6 to Fl-ATF6 after scanning is shown (below). (B) Western blot analysis of nuclear extracts from STHdhQ7/7 cells stimulated as in A. After normalizing to the loading control (lamin A/C), optical density of Nt-ATF6 bands relative to control untreated cells is shown (below). (C) Immunohistochemistry for ATF6 in striatal neurons from WT and R6/2 mice receiving DMSO or repaglinide. A diffuse intracellular ATF6 labeling is observed in WT neurons. In striatal neurons from DMSO-treated R6/2 mice, ATF6 immunoreactivity appears as a dense intracellular aggregate (arrows). In repaglinide-treated R6/2 mice, ATF6 labeling has a diffuse distribution, similar to WT neurons. Scale bar: 20 μm. (D) Western blot analysis of nuclear extracts from striatum from WT and R6/1 mice receiving DMSO (–) or repaglinide. A representative autoradiogram is shown. After quantification of the autoradiograms, ratios vs. loading control TBP were normalized to DMSO-treated WT mice for each experiment. **P < 0.01, R6/1 vs. WT; #P < 0.05, R6/1 vs. repaglinide-treated R6/1 mice (1-way ANOVA [Kruskal-Wallis], followed by Dunn’s multiple comparisons test, n = 6 mice in each group). (E) Real-time qPCR analysis of Bip mRNA in the striatum from WT and R6/1 mice receiving DMSO (–) or repaglinide, as indicated. Values are normalized relative to Hprt mRNA levels. ***P < 0.001, DMSO-treated R6/1 vs. WT; #P < 0.05, R6/1 vs. RP-treated R6/1 mice (statistics as in D, n = 7 mice in each group).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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