Human cells repair thousands of DNA lesions daily. The majority of lesions arise from the intrinsic chemical instability of DNA and include single-strand breaks and base modifications. Unrepaired lesions can obstruct DNA replication, leading to mutations and toxic DNA double-strand breaks. In non-proliferating cells (for example, post-mitotic neurons) damaged DNA bases and single-strand breaks can block transcription, leading to cell death and disease. Although defects in DNA repair are often linked to progressive neurological disorders, their precise roles in the neurological phenotypes remain elusive. Our research objectives are to: - Unravel molecular mechanisms by which mutations in DNA damage response proteins lead to progressive neurodegeneration. - Determine how DNA damage and repair contributes to disease progression in the brain. - Identify novel DNA damage response proteins required for the maintenance of homeostasis in the brain.