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

> **NIH NIH R21** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $423,500

## Abstract

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.

## Key facts

- **NIH application ID:** 10508019
- **Project number:** 1R21NS128519-01
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Mohammad Moshahid Khan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,500
- **Award type:** 1
- **Project period:** 2022-08-19 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10508019

## Citation

> US National Institutes of Health, RePORTER application 10508019, Novel DNA damage-Based Mechanisms and Therapeutics for Parkinson’s disease (1R21NS128519-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10508019. Licensed CC0.

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