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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 126 Issue 2 Pg. 627-38 (Feb 2016) ISSN: 1558-8238 [Electronic] United States
• PMID: 26752648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• Atf6 protein, mouse
• Carbamates
• Csen protein, mouse
• KCNIP3 protein, human
• Kv Channel-Interacting Proteins
• Piperidines
• Repressor Proteins
• repaglinide

Topics

• Activating Transcription Factor 6 (genetics, metabolism)
• Animals
• CHO Cells
• Carbamates (pharmacology)
• Corpus Striatum (metabolism, pathology)
• Cricetulus
• Disease Models, Animal
• HEK293 Cells
• HeLa Cells
• Humans
• Huntington Disease (genetics, metabolism, pathology)
• Kv Channel-Interacting Proteins (genetics, metabolism)
• Mice
• Neurons (metabolism, pathology)
• Piperidines (pharmacology)
• Repressor Proteins (genetics, metabolism)
• Signal Transduction