H

untington's Disease (HD) is a genetically inherited dominant neurodegenerative disorder caused by a mutation in the gene coding for huntingtin protein. There is no effective treatment and the identification of potential targets for HD therapeutic intervention thus remains a priority. The progression of HD is characterized by motor, psychiatric and cognitive symptoms whose severity varies considerably among patients. An intriguing characteristic of HD is its slowly progressive nature since, while mutant huntingtin is expressed throughout life, symptoms manifest at mid age. Therefore, it has been proposed that subtle alterations at the cellular level are likely to accumulate with time to become detrimental at later stages.

Identification of reliable and accessible biomarkers to follow disease progression and to test the effectiveness of future treatments will be beneficial to patients and will enable a personalized medicine. One of the main limitations for understanding the progression of HD is that we only have access to brain samples through post-mortem tissues, which typically reflect the final stages of the disease. Consequently, it is very important to find reliable models based on human peripheral samples that will mirror the slow and cumulative aspects of disease progression. Blood is an easy, affordable and minimally invasive source of biomarkers. However, most blood cells have a very rapid turnover and will very unlikely recapitulate the slow progressive nature of HD. Interestingly, a subset of lymphocytes, naïve T cells are long-lived post-mitotic cells, with lifespans of decades.

This project focuses on the understanding of the molecular mechanisms and the identification of peripheral biomarkers of HD. The starting hypothesis is that ribosome stalling and specialization are relevant to HD progression and that long-lived human naïve cells could recapitulate the slow progressive nature of HD and be a good peripheral model for studying such mechanisms and identifying potential biomarkers of disease progression. In this project we will employ a multidisciplinary approach that will involve front-line enabling techniques to analyze the impact of ribosome specialization and evaluate the potential and reliability of ribosome stalling related biomarkers in naïve T cells to follow HD progression.