Every human cell suffers tens of thousands of tiny nicks in its DNA every day, and when the repair system for these single-strand breaks fails, the result can be progressive brain degeneration. The researcher has already identified six rare genetic diseases caused by faulty SSB repair, including one his team discovered, and has now worked out the molecular mechanism by which unrepaired breaks damage neurons. This fills a fundamental gap: until now, no one knew exactly how a single-strand break triggers disease. The project will test whether existing drugs or new drug-like molecules can restore normal neuron function in experimental models of these rare conditions. If successful, the work could lead to treatments for these devastating inherited neurological disorders. Because SSBs are the most common form of DNA damage and accumulate with age and oxidative stress, the findings may also extend to more common neurodegenerative diseases and even normal brain ageing. This is primarily fundamental science—understanding a core cellular repair process—but with a clear clinical direction already built into the programme.
View original technical description
My laboratory is focused on understanding how breaks in the genetic material (DNA) can lead to disease. The proposed work will address exciting new hypotheses that have arisen during my current research programme concerning the mechanism/s by which unrepaired DNA single-strand breaks (SSBs), which are breaks in one strand of the DNA double helix, trigger neurodegeneration. To date, six human genetic diseases have been identified in which there is a defect in SSB repair; the latest one being identified under the auspices of my current MRC research programme (spinocerebellar ataxia autosomal recessive 26; SCAR26, which is mutated in the protein, XRCC1). Excitingly, we have discovered how unprepared SSBs trigger this disease, providing not only the first molecular explanation for how SSBs cause disease but also opening up possible new avenues for therapeutic intervention. We plan to pursue these novel discoveries in the new research programme proposed here. We will employ a combination of molecular, cellular, and physiological experimental models to build on our recent discoveries and define at the mechanistic level how SSBs cause defects in neuronal function in vitro and in vivo, and how such defects lead to neurological disease. Importantly, we will also continue to develop our work in a clinical direction, by testing the ability of existing and novel drugs/drug-like molecules for their ability to restore normal neuron function and prevent neurological diseases that arise from SSBs. Whilst we are focusing on experimental models of rare genetic diseases to address our scientific questions, the relevance of this work may extend to more common degenerative diseases and even to the normal ageing population. This is because SSBs are the commonest form of DNA damage arising in cells and are induced not only by oxidative stress (which is elevated in brain and is believed to contribute to human ageing) but as discovered in our recent work also by the normal processes by which human neurons regulate the expression of their genes.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know