DETERMINANTS OF NEURODEGENERATION IN ATAXIA TELANGIECTASIA

The aim of the research

Main researcher

DOMENICO DELIA

Partners

LORENZO MAGRASSI

Ataxia-telangiectasia (A-T) is an inherited neurodegenerative disorder with onset in early childhood.

Symptoms of the disease include cancer predisposition, immunodeficiency and early aging, although the most devastating feature is severe neuromotor dysfunction due to progressive cerebellar ataxia, which causes children to generally require a wheelchair by age 10. The pathology arises from genetic defects in the ATM protein, which is best known for its central role in the response to DNA double-strand breaks but is also involved in many other cellular pathways. Indeed, many factors are seemingly connected to the onset of the neuropathology, and although enormous progress has been made in elucidating the functions of ATM, it is still unclear what makes neurons extremely vulnerable in A-T. Recently established patient-derived induced pluripotent stem cells (iPSCs) which can differentiate into neurons offer a powerful tool for modeling the neurological disease in vitro and will be employed in this project in order to increase our understanding of the mechanisms underlying neurodegeneration in A-T. In particular, we will focus our attention on the analysis of possible transcriptional defects and hypersensitivity to neuronal stimulation in our cellular model. Moreover, we will try to establish a protocol for the in vitro differentiation of Purkinje cells, which are the most susceptible to degeneration following ATM loss, and we will transplant our cells into the rat cerebellum in order to characterize their differentiation potential and their properties in vivo. These studies will help shed light on the causes of the neuropathology in A-T and could be useful for the identification of therapeutic targets.