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 2

Reduced DREAM protein level is a neuroprotective response.

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Reduced DREAM protein level is a neuroprotective response. (A) Latency t...
(A) Latency to fall in the rotarod test for mice (n = 24–30) of the indicated genotypes at 11 and 16 weeks of age. Significant differences between genotypes were found by 2-way ANOVA followed by Tukey’s test. **P < 0.01, ****P < 0.0001 vs. WT; #P < 0.05, ##P < 0.01 vs. R6/2. (B) Percentage survival (Kaplan-Meier) of R6/2 (n = 32) and R6/2 DREAM+/– (R6/2 DR+/–) (n = 43) (upper panel) or R6/1 (n = 11) and R6/1 daDREAM mice (n = 9) (lower panel). Curves were compared by log-rank (Mantel-Cox) test (P < 0.0001). (C) Cell death as a percentage of maximum LDH released for noninfected STHdhQ111/111 cells, cells infected with a GFP-expressing lentivirus, or cells infected with a DREAM-GFP–expressing lentivirus. For each group, cell death was compared for untreated cells vs. cells exposed to vehicle or to the indicated stimuli: H2O2 (10 μM), rotenone (100 nM), or staurosporine (5 nM). Data (mean ± SEM) are derived from 3 independent experiments in quadruplicate. Statistical significance was analyzed by 2-way ANOVA followed by Tukey’s test. *P < 0.05, ****P < 0.0001 vs. basal or vs. GFP groups.