# Urate-LRRK2 interactions in Parkinson's disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $403,753

## Abstract

Urate-LRRK2 interactions in Parkinson’s disease
Project Summary/Abstract:
Although mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common
known genetic cause of Parkinson’s disease (PD), their incomplete penetrance indicates that other
genetic and environmental factors play important protective roles in LRRK2 PD. Classical epidemiology
studies of PD have identified molecular factors that may contribute to or protect against the underlying
neurodegenerative process. Among the latter, urate an endogenous antioxidant as well as the end
product of purine metabolism has emerged as a major inverse (reduced) risk factor not only for PD
onset but also for its clinical progression. A convergence of these epidemiological data with laboratory
evidence of its neuroprotective properties suggests that urate may be a mediator as well as a marker
of favorable outcomes in idiopathic PD. New biomarker findings of lower urate levels among LRRK2 PD
patients compared to people with LRRK2 mutations who have not developed PD raise the possibility
that higher levels of endogenous urate contribute to the incomplete penetrance of LRRK2 mutations.
The hypothesis is strengthened by evidence that urate protects dopaminergic neurons by activating the
Nrf2 antioxidant response pathway, which has recently been implicated in LRRK2 pathophysiology. The
current project will determine the neuroprotective potential and molecular mechanisms of urate in
laboratory models and human biomarker studies of LRRK2 PD. Through its specific aims (SAs) it will
characterize the neuroprotective effects of urate and their astrocyte dependence in cellular and animal
models of neurodegeneration in a LRRK2+ PD (SA 1). The role of Nrf2 in the neuroprotective actions
of urate and another Nrf2 activator, dimethyl fumarate (a pharmaceutical, approved for disease
modification in multiple sclerosis) will be incisively addressed through a complementary set Nrf2
knockout and Nrf2 transgene rescue studies in LRRK2+ PD models (SA 2). Lastly, the interaction
between urate and LRRK2 kinase activity (gauged by levels of auto-phosphorylated LRRK2) will be
explored in clinical cohorts of idiopathic and LRRK2 PD (SA 3). The mechanistic and clinical insights
generated by these studies may validate Nrf2 activation as a promising therapeutic strategy in LRRK2
PD, and may thereby facilitate early steps toward personalized medicine for PD. The results may also
help address a growing concern over cost-effectiveness in the field of personalized medicine because
Nrf2 activators are already available for clinical use. And of those poised for efficacy trials in LRRK2 PD
the urate precursor inosine has been developed as a non-proprietary therapeutic with foundation and
government investment. Thus the project offers realistic prospects for advancing our understanding of
PD neurobiology and treatment.

## Key facts

- **NIH application ID:** 9978147
- **Project number:** 5R01NS110879-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MICHAEL A SCHWARZSCHILD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $403,753
- **Award type:** 5
- **Project period:** 2019-08-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978147

## Citation

> US National Institutes of Health, RePORTER application 9978147, Urate-LRRK2 interactions in Parkinson's disease (5R01NS110879-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978147. Licensed CC0.

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