# LRRK2 and oxidative stress in Parkinson’s disease

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $490,660

## Abstract

Mutations in LRRK2 are the most common cause of autosomal dominant Parkinson's disease (PD) and it appears
that all such pathogenic mutations are associated with aberrantly enhanced LRRK2 kinase activity. Independent
of mutations, however, there is also evidence that increased LRRK2 kinase activity contributes to the
pathogenesis of idiopathic PD (iPD). The current project is designed to elucidate how wildtype (non-mutated)
LRRK2 kinase activity is stimulated, where in the cell this occurs, and what the downstream consequences are.
In keeping with the well-known association of iPD with oxidative stress and mitochondrial dysfunction, we focus
on these processes in relation to LRRK2. Specifically, this project examines (i) the oxidative activation of LRRK2,
(ii) the translocation of LRRK2 to mitochondria under conditions of mitochondrial stress, and (iii) LRRK2 kinase
activity-dependent oxidative stress. The overarching premise of this proposal is that oxidative stress and LRRK2
kinase activity are intimately and bidirectionally intertwined in PD pathogenesis.
The project has 3 broad Specific Aims to address these issues:
Aim 1: To elucidate the oxidative activation of LRRK2 kinase, we will (a) assess/compare WT LRRK2 activation
by physiological stressors (H2O2, 4HNE and DA) to the PD-associated toxicants: rotenone, paraquat (PQ) and
trichloroethylene (TCE); (b) Determine whether monensin & chloroquine activate LRRK2 via oxidative
mechanisms; (c) Examine the role of cysteine residues C2024/5 in oxidative LRRK2 activation.
Aim 2: To examine translocation of LRRRK2 to mitochondria, we will (a) Assess mitochondrial localization of
LRRK2 in response to various mitochondrial stressors; (b) See if translocation requires (i) mitochondrial ROS,
(ii) cytosolic ROS, (iii) LRRK2 activity or (iv) Cys2024/5; (c) Determine whether mitochondrial translocation of
LRRK2 occurs in vivo in rat models of PD; (d) Evaluate whether LRRK2 association with mitochondria is
aberrantly enhanced in human iPD brain tissue.
Aim 3: To elucidate the role of LRRK2 kinase in oxidative stress and its downstream consequences, we will (a)
Use genetic and pharmacological approaches to see if pathogenic LRRK2 mutations cause oxidative stress and
whether blocking LRRK2 kinase activity prevents oxidative stress; (b) Examine the potential role of Cys2024/5
in driving LRRK2 kinase activity-dependent oxidative stress; (c) Determine if rotenone-induced mitochondrial
ROS production is reduced by LRRK2 inhibition/knockout; (d) Determine if rotenone-induced cytosolic NOX2
activation is reduced by LRRK2 inhibition/knockout; (e) Assess ROS production in patient-derived healthy
control, iPD and G2019S mutant lymphoblastoid cells.
Together, these experiments will begin to elucidate the intimate and bidirectional relationship between oxidative
stress and LRRK2 in PD pathogenesis. By doing so, new therapeutic strategies are likely to emerge.

## Key facts

- **NIH application ID:** 10795155
- **Project number:** 1R01NS131137-01A1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** J Timothy Greenamyre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $490,660
- **Award type:** 1
- **Project period:** 2024-08-23 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795155

## Citation

> US National Institutes of Health, RePORTER application 10795155, LRRK2 and oxidative stress in Parkinson’s disease (1R01NS131137-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795155. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*