Award Title: Identifying neuroprotective mechanisms against DNA damage accrual in aging and neurodegeneration
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK.  Funding details for UK DRI programmes will be added in 2019. Genomic instability (GIN) is an important feature of neurodegeneration and a hallmark of neuronal ageing (1), that if averted could lead to prevention, delay or reversal of GIN-related neurodegenerative disease, thus representing an important therapeutic avenue.  Most mature neurons are non-replicative cells that need to live for 80+ years and all this time require the ability to deal with exogenous (e.g. chronic ionizing radiations(2, 3)) and endogenous (e.g. metabolic by-products; reactive oxygen species: ROS(4, 5)) factors that create DNA-damage (6).  These injuries can range from simple nicks or R-loops following defective transcription to highly toxic double-strand DNA breaks (DSBs) caused by factors such as ROS and other metabolic by-products (7) that can cause breakage of the DNA. In mature neurons these lesions are counteracted by the DNA-damage response (DDR) via yet not very well-defined mechanisms (6, 8).  It is proposed that failure to impede GIN formation and/or execute DNA repair will cause cell cycle re-entry, chronic inflammation, premature senescence, aggregation of proteins or cell death, processes that would lead to initiation of diverse neuropathology including loss/degeneration of motor or cognitive functions (1, 9-12).  Hence, accumulation of GIN throughout healthy life represents one of the hallmarks of neurodegeneration (13) and numerous neurodegenerative diseases including Huntington’s Disease (HD), Parkinson Disease (PD)(5,14) and Alzheimer’s Disease (AD)(15), bear hallmarks of GIN build-up. Although GIN is probably a central player in neurodegeneration either in specific pathologies or aging, to date there is no comprehensive understanding of the cause-effect relationship nor there is any approved therapy to combat neurodegeneration via maintenance of genomic stability (6). On the other hand it needs to be noted that because at molecular/GIN level there is a strong negative correlation between cancer and neurodegeneration (16), finding the specific feed-back loops that are common can allow the repurposing of cancer drugs for neuropathology (8). The overall AIM of the Balmus Laboratory at UK-DRI will be to identify the genetic factors and the specific endogenous lesions involved in GIN-related neurodegeneration in mature neurons and how these molecular processes contribute to neurodegenerative disease (i.e. death via cell cycle re-entry) such as PD or AD as well as aging. Moreover, by finding genetic factors that can modify the accumulation of GIN and thus control neuronal homeostasis we aim to find the intervention points (biomarkers and druggable targets) that can protect human mature neurons from GIN built-up and thus achieve protection, delay or reversal of neurodegeneration.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: NEUROLOGICAL