ROLE OF THE PROLYL-ISOMERARE PIN1 IN HUNTINGTON’S DISEASE

Huntington’s disease is an inherited neurodegenerative disorder that usually begins in mid-life and affects ~1 in 10,000 individuals. HD patients show severe neurological symptoms that gradually worsen with age. After ten years from the onset of the disease, patients lose their intellectual abilities and must rely on total care for their activities. Death usually occurs for asphyxia or hearth attack. The gene responsible for the disease has been identified 10 years ago and, since then, a number of progresses have been done in understanding the molecular and cellular basis of the disease. HD gene product, named Huntingtin, when normal has protective role in neurons, but when mutated gains toxic properties, and becomes responsible for the neuro-degeneration observed in Huntington disease. In particular, its activities lead to neuronal death through both oxidative stress and cellular alterations. Notably, these events involve activation of the factor p53, also known as guardian of the genome for its role in inducing cell death in response to diverse stresses. Our group has demonstrated that the protein Pin1 binds to p53 and modulates its functions in response to several cellular damaging agents. In this project we propose to study the role of Pin1 in regulating the neuro-protective functions of normal Huntingtin and the toxic effects induced by the mutant form of Huntingtin. We are confident that our study will contribute to a better understanding of the molecular mechanisms of Huntingtin function and will lead to the identification of new modulators of the activities of mutant Huntingtin as suitable targets for therapeutic intervention against this devastating neurodegenerative disease.