Novel DNA damage-Based Mechanisms and Therapeutics for Parkinson’s disease

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Parkinson’s disease (PD) is a common and devastating neurodegenerative disorder that affects up to one million individuals in the US and 10 million or more worldwide. Currently, there are no therapeutic interventions that stop or slow the progression of PD. Several hypotheses have been proposed as causative of PD, including, loss of dopaminergic neurons, mitochondrial dysfunction, oxidative stress, and α-synuclein deposition (Lewy bodies), but the exact causes of PD are still unclear. More recent studies have highlighted the role of nuclear DNA damage, particularly, nuclear DNA double-strand breaks (DNA DSBs), in the progression of neuronal loss in a broad spectrum of human neurodegenerative diseases including PD. However, it is not clear if nuclear DNA DSBs 1) serve as a primary driver of PD or simply occur concomitant with disease progression, and 2) confer an additional risk factor for PD development. Although, a role of DNA DSBs in neurological disorders is fairly-well studied, the mechanisms of its involvement in neurodegeneration and behavioral deficits during PD conditions are unknown. This represents a gap in our knowledge, which this proposed study will address. To define the role of DNA DSBs in PD, we have generated and characterized a novel mouse model system. We have previously demonstrated that a deficiency of CDKN1A-interacting zinc finger protein 1 (CIZ1), a nuclear protein, leads to sustained DNA DSBs, and cell death in irradiated mouse embryonic fibroblasts. The brains of aged CIZ1KO mice show overt and sustained DNA DSBs, oxidative stress, and cell death, all of which are found in PD. Furthermore, our preliminary findings demonstrated, elevated DNA DSBs and reduced CIZ1 levels in the brains of Parkinson’s patients and mouse model of PD. Our central hypothesis is that the increased accumulation of nuclear DNA DSBs in the brain contributes to neurodegeneration and behavioral deficits in Parkinsonian mice and that DNA repair plays a critical role in alleviating the pathological consequences in PD. The objectives of this application are 1) to understand the role of nuclear DNA DSBs in PD pathogenesis and how they relate to the loss of dopaminergic neurons and 2) to test the therapeutic benefits of DNA repair activators in alleviating post-PD neuropathological symptoms. We propose two specific aims to test our hypothesis. In Aim 1, we will define the role and mechanisms of DNA DSBs in the progression of neurodegeneration and behavioral dysfunction in a mouse model that recapitulates key features of PD. In Aim 2, we will determine the therapeutic benefits of DNA repair activators to effectively suppress DNA damage-mediated neurodegeneration and behavioral deficit in mouse models of PD. Our proposal is expected to identify the potential contribution of DNA DSBs in PD and determine the therapeutic benefits of targeting the DNA damage response in alleviating the pathological consequences in PD.