DNA SINGLE STRAND BREAKS AND NEURODEGENERATION: THE ROLE OF APRATAXIN AND SENATAXIN

Human syndromes whose gene products function in DNA damage response and repair are characterized by defects in development or maintenance of the nervous system. Defects in the repair of DNA single-strand breaks (SSBs) were described only recently in diseases that are classic recessive spinocerebellar ataxias without any extraneurological features. These syndromes, and specifically Ataxia with Oculomotor Apraxia type 1 and 2 (AOA1 and AOA2, respectively), will constitute a good model for understanding the biological mechanisms linking DNA damage to neurodegeneration. The aim of our project is to define the role of aprataxin and senataxin, two recently detected proteins that appear to be involved in the DNA repair, in this pathway. These proteins are defective in patients with AOA1 and AOA2, respectively. We will treat the cells from patients suffering these diseases, as well as from their carriers and wild-type relatives, with drugs inducing or inhibiting different type of DNA damage. We will also study, by means of new proteomic tools, the interactions of the two proteins between them and with other proteins involved in the same responses. We expect to find an explanation on why neuronal cells defective in these proteins undergo dramatic apoptosis leading to neurodegeneration.