title: 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.forename: José R
authors.initials: JR
authors.lastname: Naranjo
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.forename: Diego
authors.initials: D
authors.lastname: Villar
authors.forename: Paz
authors.initials: P
authors.lastname: González
authors.forename: Xose M
authors.initials: XM
authors.lastname: Dopazo
authors.forename: Javier
authors.initials: J
authors.lastname: Morón-Oset
authors.forename: Elena
authors.initials: E
authors.lastname: Higueras
authors.forename: Juan C
authors.initials: JC
authors.lastname: Oliveros
authors.forename: María D
authors.initials: MD
authors.lastname: Arrabal
authors.forename: Angela
authors.initials: A
authors.lastname: Prieto
authors.forename: Pilar
authors.initials: P
authors.lastname: Cercós
authors.forename: Teresa
authors.initials: T
authors.lastname: González
authors.forename: Alicia
authors.initials: A
authors.lastname: De la Cruz
authors.forename: Juan
authors.initials: J
authors.lastname: Casado-Vela
authors.forename: Alberto
authors.initials: A
authors.lastname: Rábano
authors.forename: Carmen
authors.initials: C
authors.lastname: Valenzuela
authors.forename: Marta
authors.initials: M
authors.lastname: Gutierrez-Rodriguez
authors.forename: Jia-Yi
authors.initials: JY
authors.lastname: Li
authors.forename: Britt
authors.initials: B
authors.lastname: Mellström
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D003412:Cricetulus; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010880:Piperidines / Q000494:pharmacology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; C497112:Atf6 protein, mouse; D002219:Carbamates; C496756:Csen protein, mouse; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; D010880:Piperidines; D012097:Repressor Proteins; C072379:repaglinide