FUNCTIONAL CHARACTERIZATION OF MISSENSE MUTATIONS IN SCA28 PATIENTS, DEVELOPMENT OF A MOUSE MODEL OF THE DISEASE, AND SCREENING OF CANDIDATE GENES FOR CEREBELLAR ATAXIA

The term ataxia refers to poor coordination of movement. Hereditary forms of ataxia are a group of genetic disorders producing a slowly progressive loss of gait coordination and are often associated with poor coordination of hand and eye movement, and speech. Genetic forms can be autosomal dominant (such as Spinocerebellar ataxias or SCA) or autosomal recessive (Friedreich’s ataxia). Twenty-seven major types of autosomal dominant hereditary SCAs have now been mapped. Our group has contributed to discover SCA28. The next step to search for a therapy is to understand the molecular basis of a disease. With the present project we aim to follow some observations coming both from the literature and from our results to understand how SCA28 mutations cause the disease: 1) the SCA28 protein is localized in the mitochondria, the energy-suppliers of the cells; we will investigate if the protein is reduced in its levels, and if the function of the mitochondria is hampered; 2) the defects (mutations) we have found in several families with SCA28 are all clustered in the same region of the protein: are they impairing a specific function, or are they important to take contact with other proteins - that may be good targets for therapy- ? We will address these questions measuring one function of the SCA28 protein, its ability to cut other proteins (proteolytic activity), and we will search for interacting partners, evaluating the effect of the mutations on the binding capacity. 3) A murine model is a key step to better understand the disease, and it will be fundamental to test for therapies; 4) The search for interacting partners will lead us to good candidates for other forms of SCA, that we will screen. It must be taken in consideration that one half of the hereditary forms of SCA are gene orphan. This project is therefore aimed to find possible ways that may be important for the therapy of this and possibly other forms of neurodegenerative disease.