# LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $460,750

## Abstract

Project Summary
Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused primarily by the
degeneration of dopaminergic neurons in the substantia nigra. Mutations in the leucine-rich repeat kinase 2
(LRRK2) gene cause late-onset, autosomal dominant PD, and LRRK2 coding and non-coding variants are
associated with risk of sporadic PD. LRRK2 has emerged has an important therapeutic target for treating PD
and therefore it is critical to understand the key mechanisms underlying disease-linked mutations. LRRK2 is a
large multi-domain protein containing Ras-of-Complex (Roc) GTPase and protein kinase enzymatic domains
separated by a C-terminal-of-Roc (COR) domain. GTP-binding via the Roc domain is critical for normal kinase
activity. Familial LRRK2 mutations cluster within the Roc (R1441C/G/H), COR (Y1699C) and kinase (G2019S,
I2020T) domains where they commonly enhance the phosphorylation of a subset of Rab GTPase substrates in
cells. Roc-COR domain mutations act indirectly on kinase activity by impairing GTP hydrolysis and promoting
the GTP-bound `on' state. The GTPase and kinase domains represent promising targets for inhibiting LRRK2.
While familial LRRK2 mutations share the capacity to induce neuronal damage in cultured cells, their effects in
animal models are less certain due to a lack of robust neurodegenerative phenotypes. In addition, how the two
enzymatic activities contribute to neuronal damage in vivo induced by familial LRRK2 mutations is poorly
understood. We have recently developed an adenoviral-mediated gene transfer model in adult rats where
G2019S LRRK2 induces nigrostriatal pathway dopaminergic neurodegeneration through a kinase-dependent
mechanism. In the present application, we propose to exploit this robust and rapid rodent model to determine
whether kinase activity is commonly required for neurodegeneration induced by familial mutations (R1441C,
Y1699C and G2019S) or PD risk variants (G2385R) in LRRK2 by genetic and pharmacological kinase inhibition
(Aim 1.1). The contribution of Rab phosphorylation to neuronal damage induced by mutant LRRK2 is not known.
We will determine the neuroprotective effects of globally reducing Rab phosphorylation in mutant LRRK2
neuronal and adenoviral rat models by overexpressing a novel Rab-specific phosphatase, PPM1H (Aim 1.2).
Knockdown of PPM1H will explore whether increasing Rab phosphorylation is sufficient to phenocopy the
neurotoxic effects of mutant LRRK2. Our studies will further explore whether genetically modulating GTPase
activity can provide a common neuroprotective mechanism against different familial LRRK2 mutations in rodents
(Aim 2.1). In particular, we will evaluate hypothesis-testing mutations that increase GTP hydrolysis and promote
the GDP-bound `off' state of LRRK2. Finally, we will explore how the native interactome of LRRK2 in neurons is
regulated by the GTPase cycle to identify novel protein targets that interact with LRRK2 in its GDP- or GTP-
bound ...

## Key facts

- **NIH application ID:** 10786027
- **Project number:** 5R01NS120489-04
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Darren John Moore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $460,750
- **Award type:** 5
- **Project period:** 2020-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10786027

## Citation

> US National Institutes of Health, RePORTER application 10786027, LRRK2 Enzymatic Mechanisms of Neurodegeneration in Parkinson's Disease (5R01NS120489-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10786027. Licensed CC0.

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