# Mechanisms of mitochondrial genome integrity in familial and idiopathic Parkinson's disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $28,956

## Abstract

Abstract
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder and over ten million
people worldwide are living with PD. To date, treatments are only symptomatic; they do not alter the inexorable
progression of the disease. The most common cause of familial and idiopathic PD are mutations in leucine-rich
repeat kinase 2 (LRRK2). LRRK2-associated and idiopathic PD demonstrate mitochondrial impairment, however
our understanding of the molecular underpinnings of mitochondrial dysfunction in PD is limited. In our efforts to
understand the underlying mechanisms driving mitochondrial dysfunction, we found that mitochondrial DNA
damage is a shared phenotype amongst both LRRK2-associated and idiopathic PD. Unrepaired mitochondrial
DNA damage can have major adverse cellular effects, impacting genetic and protein instability, compromising
bioenergetic function, increasing reactive oxygen species, and triggering cell death. Recent preliminary studies
by the Sanders lab has found that blocking kinase activity of ATM (a kinase that functions to sense, signal and
promote repair of DNA damage) rescues PD-induced mitochondrial DNA damage. We further observed that
ATM is activated and initiates the DNA damage response pathway. Interestingly, mitochondrial DNA repair
capacity is impaired with a concomitant increase in specific mitochondrial oxidative DNA lesions. The
overarching goal of the parental grant to understand how dysfunctional LRRK2 triggers the ATM-mediated DNA
damage response pathway, which impairs mitochondrial DNA repair capacity, leading to an increase in
mitochondrial DNA damage, ultimately promoting downstream pathogenic PD cascades. Specific to this
research supplement, we have discovered that the role of mutant LRRK2 extends to nuclear DNA damage.
Based on this data, Dr. Gonzalez-Hunt will determine the molecular identity of the nuclear DNA lesions that are
in common between LRRK2 and idiopathic PD. She will learn new technical expertise and methodology, publish
impactful research and obtain the key preliminary data for competitive K grants to launch an independent
scientific career. Overall this project will directly complement the parental grant and ongoing experiments in the
lab to understand shared pathways driven by LRRK2 dysfunction, in order to provide new insights into PD
pathophysiology and consequently lead to new therapies.

## Key facts

- **NIH application ID:** 10353124
- **Project number:** 3R01NS119528-01S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** LAURIE H SANDERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $28,956
- **Award type:** 3
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10353124

## Citation

> US National Institutes of Health, RePORTER application 10353124, Mechanisms of mitochondrial genome integrity in familial and idiopathic Parkinson's disease (3R01NS119528-01S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10353124. Licensed CC0.

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