Molecular Characterisation of Single-Strand Break Repair and Related Responses and their Role in Neuroprotection

DNA breakage can lead to gene damage, cancer, and cell death, if not repaired rapidly and accurately. The commonest type of damage arising in cells is the single-strand break; a breakage of one of the two strands that comprise the DNA double helix. Recently, we have identified a direct link between an individual?s ability to repair single-strand breaks and hereditary neurodegenerative disease. These diseases are termed spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and ataxia oculomotor apraxia-1 (AOA1) and harbour mutations in the DNA repair genes Tdp1 and APTX, respectively. SCAN1 and AOA1 are associated with the progressive degeneration of specific parts of the brain (particularly the cerebellum), resulting ultimately in an inability of affected individuals to walk properly or to control normal movement. In this programme of work we will advance and extend our understanding of the single-strand break repair process, and address directly the relationship between this process and neurological function. This work will shed light on the link between DNA damage and neurodegeneration, and will hopefully provoke novel approaches for the treatment of certain types of neurological disease.