GENETIC DISSECTION OF THE ROLE OF RAS/ERK SIGNALLING IN THE AETIOLOGY OF HUNTINGTON’S DISEASE

Both in human patients and in animal models of Huntington’s Disease (HD), a selective striatal neurodegeneration can be observed, together with progressive motor and cognitive impairments. Aim of the present research is to study the involvement of Ras/ERK signaling pathway in the disruption of striatal functionality that developes during HD and leads to striatal neurodegeneration. To do this, animals (mice) in which the expression of some factors acting inside this pathway has been genetically abolished will be used. In particular the guanine nucleotide exchange factor Ras-GRF1 and the extracellular signal regulated kinase ERK1 will be considered. Subsequently animals will be used in which the expression of the guanine nucleotide exchange factor Sos1 has been abolished selectively into striatal nuclei (conditional mutants) or in which, always in striatal nuclei, the reversible expression of a dominant negative isoform of the transcription factor CREB has been induced. Those animals will be subjected to chronic administration with 3-nitropropionic acid, a mitochondrial toxin that is able to riproduce in treated animals a condition similar to that observed in HD human patients. At different time points during the treatment, the following variable will be considered: 1)neurodegeneration rate inside the striatum. 2)Locomotor alteration induced by the treatment. Animals will undergo locomotor activity tasks. 3)Cognitive functions decline. Subjects will undergo memory tasks. 4)Electrophysiological analysis of the cortico-striatal pathway.