# Mechanisms of LRRK2 Mediated Neurotoxicity

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $402,500

## Abstract

Supplement for R01-NS064934 “Mechanisms of LRRK2 Neurotoxicity”
Abstract- LRRK2 in tauopathy
 Parkinson's disease (PD) and related Lewy body diseases, including dementia with Lewy bodies (DLB),
are common causes of Alzheimer's disease related dementias (ADRDs). Although therapies that might slow or
halt disease have not been found, recent discoveries from human genetics, post-mortem tissue studies, and
disease models have zeroed in on a few genes hypothesized to control disease progression. Tens of
thousands of Americans harbor missense mutations in the LRRK2 gene that increase LRRK2 kinase activity
and cause PD. Although LRRK2-linked disease is clinically indistinguishable from idiopathic PD, LRRK2
mutation carriers often demonstrate prominent Alzheimer's-type tau pathology, sometimes without traces of
alpha-synuclein pathology, in vulnerable regions through the brain.
 In our ongoing efforts in this project to define the role of LRRK2 in neurodegeneration, we have
identified critical interactions between LRRK2 and alpha-synuclein in both neurons and immune cells that both
express LRRK2 protein. In this Supplement, we propose the exploration of a direct LRRK2-tau interaction in
LRRK2 mediation of Alzheimer's type-tau inclusion spread and neuroinflammation. In supplement to our
ongoing work, we will test whether LRRK2 kinase inhibition impairs tau inclusion formation and spread in the
brain. In complement to kinase inhibition, we will determine whether LRRK2 kinase activation via genetic
mutations in the LRRK2 gene promotes tau inclusions and deleterious pro-inflammatory responses. These
studies will help us provide a framework to better understand whether a strong connection exists between
LRRK2 and tau pathology found in Alzheimer's disease. Our work may lead to the consideration of tauopathies
and Alzheimer's disease (AD) as novel indications for LRRK2-directed therapies.

## Key facts

- **NIH application ID:** 10117999
- **Project number:** 3R01NS064934-11S1
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Andrew B West
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 3
- **Project period:** 2018-11-01 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10117999

## Citation

> US National Institutes of Health, RePORTER application 10117999, Mechanisms of LRRK2 Mediated Neurotoxicity (3R01NS064934-11S1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10117999. Licensed CC0.

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