ROLE OF THE PROLYL-ISOMERASE PIN 1 IN HUNTINGTON’S DISEASE

Huntington’s disease is an inherited neurodegenerative disorder that usually begins in mid life and that affects ~1 in 10,000 individuals. Affected individuals show severe neurological symptoms that gradually worsen with age. After ten years from the onset of the disease patients lost their intellectual abilities and must rely on total care for their activities. Death usually occurs for asphyxia or heart attack. The gene responsible for the disease has been identified in 1993 and it codes for a protein named huntingtin (Htt). Since then, a number of progresses have been done in the understanding of the molecular and cellular basis of the disease. The neurodegeneration observed in Huntington disease involves mitochondrial dysfuction oxidative stress, and alteration of transcriptional program. Notably the transcription factor p53, also known as the guardian of our genome for its role in inducing apoptosis in response to cellular stress, have been show to mediate some of the toxic effects of the mutant (Htt). Our group has demonstrated that the protein Pin1 binds to p53 and modulates its apoptotic and transcriptional function in response to several cellular damaging agents. In this project we propose to study the role of Pin1 in regulating the neuroprotective functions of normal Htt and the toxic effects induced by mutant Htt. We are confident that our study will contribute to a better understanding of the molecular mechanisms involved in Htt function and will lead to the identification of new modulators of the mutant Htt function as suitable targets for therapeutic intervention against this devastating neurodegenerative disease.