Deregulated intracellular Ca2+ homeostasis underlies synaptic dysfunction and is a common feature in neurodegenerative processes. DREAM/calsenilin/ KChIP-3 is a multifunctional Ca2+ binding protein with specific functions in different subcellular compartments. In the nucleus, the Ca2+-free form of DREAM binds tightly to DRE sequences in the DNA and controls the expression of several genes related to Ca2+ homeostasis, neuronal excitability and neuronal survival. DREAM mutants unable to respond to Ca2+ and/or cAMP will disturb gene regulation leading to changes in the physiology of the synapses that might be determinant for or predispose to neuronal damage and death. We have used transgenic mice overexpressing dominant active DREAM mutants, i.e., insensitive to Ca2+, and DREAM deficient mice to assess the role of DREAM in the onset of unbalanced motor coordination and neurodegenerative processes found in chemically- or genetically-induced mouse models of Huntington disease (HD). In addition, we have tested drugs able to bind to DREAM for an effect on the onset and progression of motor dysfunction in the R6/2 mouse model of HD. Funded by grants from Fundacion LaCaixa, CEE (LSHM-CT-2004-512039), Era-Net-SAF2008- 04753-E y CIBERNED.
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