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

Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

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 4

Repaglinide ameliorates the HD phenotype.

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Repaglinide ameliorates the HD phenotype. (A) Latency to fall in the rot...
(A) Latency to fall in the rotarod test of mice of the indicated genotypes and age, exposed chronically to vehicle (DMSO) or repaglinide. DMSO-treated R6/2 mice were significantly different from WT controls at all ages, and repaglinide-treated R6/2 differed from repaglinide-treated WT mice at all ages except at 17 weeks, when there was only a slight, nonsignificant improvement. ***P < 0.001, ****P < 0.0001 vs. WT; #P < 0.05, ###P < 0.001 vs. R6/2 (2-way ANOVA, Sidak’s post test; n = 13–17). (B) Nuclear magnetic resonance analysis of striatal volume in 18-week-old mice of indicated genotypes. *P < 0.0159, WT-DMSO vs. R6/2-DMSO; #P < 0.0303, R6/2-DMSO vs. R6/2-repaglinide (Mann Whitney U test; n = 4–7). (C) Body weight progression in male mice of the indicated genotypes exposed to DMSO or repaglinide. No significant differences (2-way ANOVA, Tukey’s multiple comparison test) were found within groups of untreated or repaglinide-treated mice (n = 10). (D) Cell death, as a percentage of maximum LDH released by DREAM-expressing STHdhQ111/111 cells. Cells were exposed to vehicle or repaglinide (100 nM) and stimulated with H2O2 (10 μM) or rotenone (100 nM). Data from 3 (rotenone) or 7 (H2O2) independent experiments in quadruplicate were analyzed by 2-way ANOVA followed by Tukey’s test. ****P < 0.0001. (E) Effect of repaglinide on LDH release from N2a neuroblastoma cells (n = 4) after H2O2 exposure (20 μM). A 4-parameter (variable slope) nonlinear curve fitting resulted in an IC50 of 88.79 ± 1.39 nM for repaglinide.