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 1

DREAM expression is reduced in murine in vivo and in vitro HD models and in HD patients.

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DREAM expression is reduced in murine in vivo and in vitro HD models and...
(A and B) Western blot analysis of DREAM protein levels in striatum from R6/1 (A) and R6/2 mice (B) and corresponding WT littermates at the indicated weeks after birth. Five mice were analyzed in each group. Black arrowheads, DREAM immunoreactive band; white arrowheads, nonphosphorylated ERK1/2 loading control. After densitometric analysis, band intensity ratio vs. loading control was normalized to corresponding WT. Significant differences compared with WT were calculated using 1-way ANOVA (Kruskal-Wallis), followed by Dunnett’s multiple comparisons test or Mann-Whitney U test (##P = 0.0079) when comparing 2 groups (in B, 16 weeks). *P < 0.05; **P < 0.01. (C) Western blot analysis of DREAM levels in STHdhQ cells. DREAM-specific band intensity is reduced in heterozygous (Q7/111) compared with WT (Q7/7) cells and is below the detection limit in homozygous (Q111/111) cells. Black arrowhead, DREAM immunoreactive band; white arrowhead, α-tubulin loading control. (D) Western blot analysis of DREAM levels in striatal samples from controls (n = 5) and HD patients (n = 6). The corresponding brain bank code number (BCPA-) is shown below each lane. The DREAM-specific band (black arrowhead) was scanned, and intensity ratio vs. loading control (nonphosphorylated Erk1/2, white arrowhead) is shown (right). **P = 0.0019, Mann-Whitney U test. Black arrowheads (A–D) indicate the DREAM-specific band (Ab 670); white arrowheads show the loading control (ERK1/2 in A, B, and D; β-actin in C).