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.
Highlights
Huntington’s disease is a devastating, dominantly inherited neurodegenerative disorder caused by expansion of the number of CAG triplets in the first exon of the huntingtin gene
Neuronal expression of daDREAM in daDREAM transgenic mice resulted in a complex phenotype that shows i) loss of recurrent inhibition and enhanced Long-term potentiation (LTP) in the dentate gyrus as well as impaired learning and memory [13], ii) changes in the expression of specific activitydependent transcription factors in the hippocampus, including Npas4, Nr4a1 and c-Fos; in addition, these mice have iii) changes in the expression of genes related to the cytoskeleton such as Arc, formin 1 and gelsolin, which are responsible for specific changes in dendritic arborization and spine density in CA1 pyramidal neurons and granule cells of the dentate gyrus [14]
Impaired short- and long-term memory were observed in 20-week-old R6/1 mice, chronic repaglinide administration had no effect on cognition loss at this disease stage (Fig. 1b); repaglinide effectively reduced the post-prandial increase in circulating glucose levels in 20-week-old R6/1 mice (Fig. 1c)
Summary
Huntington’s disease is a devastating, dominantly inherited neurodegenerative disorder caused by expansion of the number of CAG triplets in the first exon of the huntingtin (htt) gene. Neuronal expression of daDREAM in daDREAM transgenic mice resulted in a complex phenotype that shows i) loss of recurrent inhibition and enhanced LTP in the dentate gyrus as well as impaired learning and memory [13], ii) changes in the expression of specific activitydependent transcription factors in the hippocampus, including Npas, Nr4a1 and c-Fos; in addition, these mice have iii) changes in the expression of genes related to the cytoskeleton such as Arc, formin 1 and gelsolin, which are responsible for specific changes in dendritic arborization and spine density in CA1 pyramidal neurons and granule cells of the dentate gyrus [14] Together these changes recapitulate the role of DREAM in structural plasticity in the hippocampus
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