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Defective DNA Damage Responses in Dominant Neurodegenerative Diseases

Periodic Reporting for period 3 - SIDSCA (Defective DNA Damage Responses in Dominant Neurodegenerative Diseases )

Reporting period: 2019-10-01 to 2021-03-31

The issue addressed with this programme of research is whether altered/abnormal responses to DNA damage underpin a range of common human neurodegenerative diseases associated with motor coordination defects (ataxia), dementia, and motor neurone disease. This is important for society because as the ageing population increases the impact of neurodegeneration on health-span, quality of life, and health provision will increase accordingly. The results of this work will provide both scientific understanding of these diseases and hopefully open up new therapeutic avenues to explore.
We have made excellent progress in addressing possible involvement of ataxia/neurodegeneration genes in the DNA damage response, during the first reporting period, employing a library of small interfering RNA's to disrupt disease genes of interest in order to examine their impact on levels of DNA damage signalling and DNA damage responses, both at levels of endogenous DNA damage and following exposure to exogenous genotoxins relevant to our environment. This screen has so far has enabled us to shortlist a number of diseae-related human genes for further analysis. In addition, we have identified a novel role for one DNA damage sensor (denoted PARP1) during normal cell growth and cell division that was unexpected. During the next period we will conduct additional screens and assays and extend our analysis to a broader range of neurodegenerative diseases in which the response to DNA strand breaks may be a factor (Huntington’s disease, Alzheimer’s disease, Parkinson’s disease). We have also been collecting disease relevant cell lines from those genes of particular interest during this first Programme reporting period, to confirm the presence/absence of phenotypes in the diseased cells themselves. Our work on the relationship between PARP activation and SSBs also led to a remarkable an unexpected discovery that the primary source of activation of this critical DNA damage sensor molecule in proliferating cells are Okazaki fragment intermediates of DNA replication. This work, which is driven by ERC staff, is now in press in the high profile/high impact journal, Molecular Cell.
As indicated above, we have begun to identify those more common neurodegenerative diseases for which we have preliminary evidence that cellular responses to endogenous types of DNA damage may be defective. This has led already to advances beyond the state-of-the art, including the work in press in Molecular cell. It is our expectation that by the end of the project we will have established which 'common' neurodegenerative disease have an underlying component of altered DNA damage response to their pathology, and that we will identify possible new therapeutic in-roads to pursue in the future.