Inhibition of DREAM-ATF6 interaction delays onset of cognition deficit in a mouse model of Huntington's disease.

Abstract

The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) is a multifunctional neuronal calcium sensor (NCS) that controls Ca2+ and protein homeostasis through gene regulation and protein-protein interactions. Downregulation of DREAM is part of an endogenous neuroprotective mechanism that improves ATF6 (activating transcription factor 6) processing, neuronal survival in the striatum, and motor coordination in R6/2 mice, a model of Huntington's disease (HD). Whether modulation of DREAM activity can also ameliorate cognition deficits in HD mice has not been studied. Moreover, it is not known whether DREAM downregulation in HD is unique, or also occurs for other NCS family members. Using the novel object recognition test, we show that chronic administration of the DREAM-binding molecule repaglinide, or induced DREAM haplodeficiency delays onset of cognitive impairment in R6/1 mice, another HD model. The mechanism involves a notable rise in the levels of transcriptionally active ATF6 protein in the hippocampus after repaglinide administration. In addition, we show that reduction in DREAM protein in the hippocampus of HD patients was not accompanied by downregulation of other NCS family members. Our results indicate that DREAM inhibition markedly improves ATF6 processing in the hippocampus and that it might contribute to a delay in memory decline in HD mice. The mechanism of neuroprotection through DREAM silencing in HD does not apply to other NCS family members.

• Authors: Alejandro López-Hurtado, Daniel F Burgos, Paz González, Xose M Dopazo, Valentina González, Alberto Rábano, Britt Mellström, Jose R Naranjo
• Journal: Molecular brain (Mol Brain) Vol. 11 Issue 1 Pg. 13 (03 09 2018) ISSN: 1756-6606 [Electronic] England
• PMID: 29523177 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• Atf6 protein, mouse
• Carbamates
• Kv Channel-Interacting Proteins
• Neuronal Calcium-Sensor Proteins
• Piperidines
• repaglinide

Topics

• Activating Transcription Factor 6 (metabolism)
• Animals
• Carbamates (administration & dosage, pharmacology, therapeutic use)
• Cognition Disorders (drug therapy, metabolism, pathology)
• Disease Models, Animal
• Hippocampus (pathology)
• Humans
• Huntington Disease (drug therapy, metabolism, pathology)
• Kv Channel-Interacting Proteins (metabolism)
• Memory Disorders (drug therapy, metabolism)
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuronal Calcium-Sensor Proteins (metabolism)
• Neurons (metabolism, pathology)
• Piperidines (administration & dosage, pharmacology, therapeutic use)
• Rotarod Performance Test