Description and Validation of New Therapeutical Targets to Prevent Neurodegenertlion and Cognitive Deficits in Huntington's Disease

Laburpena

Understanding the molecular underpinnings of neuronal dysfunction and degeneration involved in Huntington’s disease is a goal of increasing urgency for society and scientific community. In this Thesis we have studied different proteins and signaling pathways, specifically altered by the presence of mutant huntingtin, as new potential candidates to develop pharmacological strategies to treat or delay motor and cognitive deficits in Huntington’s disease. AIM 1. To study the contribution of CBP/CREB pathway in the cognitive deficits present in Huntington’s disease. AIM 2. To study the molecular mechanisms involved in neurotrophic support dysfunction in Huntington’s disease. 2.1. To analyze the role of p75NTR/TrkB receptors in the major striatal vulnerability in Huntington’s disease. 2.2. To study the role of p75NTR in cognitive deficits in Huntington’s disease. AIM 3. To study the molecular mechanisms involved in corticostriatal dysfunction in Huntington’s disease. 3.1. To characterize corticostriatal deficits in HD mouse models and analyze the role of Kalirin-7 in the alteration of corticostriatal excitatory synapses in HD. AIM 4. To study the role of Cdk5 in cognitive deficits in Huntington’s disease. AIM 5. To study the role of D1R-H3R heteromers in neuronal cell death and cognitive deficits in Huntington’s disease.