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Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

AuthorsNaranjo, José Ramón; Villar, Diego; González Pérez, Paz; Dopazo, Xose M.; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C.; Arrabal, María D.; Prieto, Ángela CSIC; Cercós, Pilar CSIC; González, Teresa; Cruz, Alicia de la CSIC ORCID; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen CSIC ORCID; Gutiérrez-Rodríguez, Marta CSIC ORCID ; Mellström, Britt
Issue Date2016
PublisherAmerican Society for Clinical Investigation
CitationJournal of Clinical Investigation 126(2): 627-638 (2016)
AbstractDeregulated 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.
Publisher version (URL)https://doi.org/10.1172/JCI82670
Identifiersdoi: 10.1172/JCI82670
e-issn: 1558-8238
issn: 0021-9738
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