# Molecular regulation of LRRK2 in Parkinson's disease

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2021 · $358,750

## Abstract

Parkinson's disease (PD) is recognized as the most common movement disorder. The cardinal symptoms
of PD are caused by the progressive degeneration of dopaminergic (DA) neurons in substantia nigra pars
compacta (SNpc) and accompanying striatal pathology. Mutations in LRRK2 are known to be the most
common genetic causes of PD. Given its strong genetic links and compelling drug ability, LRRK2 represents a
clear target for therapeutic development. However, the mechanisms that regulate LRRK2 function remain
unclear. Moreover, LRRK2 regulation in striatal pathology and striatal-dependent behaviors remains largely
elusive despite high expression of LRRK2 in the striatum. The LRRK2 protein includes two important
enzymatic domains: a ROC (Ras of Complex) GTPase domain and a kinase domain. Disease causing
mutations are found in both GTPase and kinase domains, indicating the importance of both GTPase and
kinase activities of LRRK2. To date studies have focused largely on the kinase activity of LRRK2 while
attention on the GTPase domain is limited. LRRK2 is a guanine nucleotide-binding protein, but the mechanism
of direct regulation of its GTPase domain is unclear. Conventional guanine nucleotide-binding proteins are
typically regulated by GTPase-activating proteins (GAPs) and guanine nucleotide-exchange factors (GEFs).
Some guanine nucleotide-binding proteins can be activated by nucleotide-dependent dimerization (GAD).
Whether LRRK2 is regulated by GAPs and GEFs or by GAD has been actively investigated. We have
previously identified the first GAP ArfGAP1 for LRRK2 in vitro and in vivo. Recently we discovered a potential
physiological GEF for LRRK2. It has similar expression patterns with LRRK2 in nigrostriatal pathway, interacts
with LRRK2 and regulates LRRK2 neurotoxicity. Based on the preliminary observations, our central hypothesis
is that this GEF serves as a physiological GEF for LRRK2 to increase LRRK2 GTP binding activity, regulate
LRRK2 cellular function and LRRK2-induced striatal pathology and related behavioral deficits. The objective of
this study is (1) to identify and characterize the first physiological GEF for LRRK2, (2) to determine how this
GEF regulates LRRK2 function, and (3) to explore the regulation of this GEF on LRRK2 in striatal pathology
and related behavior. Accomplishment of this study will lead to understanding how the GTPase function of
LRRK2 is regulated and to determining whether this regulation affects the actions of LRRK2 in striatum. The
LRRK2 GTPase, GAP or GEF activities would be served as new therapeutic targets, which is distinct from
direct kinase inhibition of LRRK2. New knowledge regarding this aspect of LRRK2 biology will advance our
understanding of the physiologic and pathophysiologic actions of LRRK2 as well as potential identification of
novel targets for future pharmacologic intervention.

## Key facts

- **NIH application ID:** 10308145
- **Project number:** 7R01NS112506-02
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Yulan Xiong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $358,750
- **Award type:** 7
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10308145

## Citation

> US National Institutes of Health, RePORTER application 10308145, Molecular regulation of LRRK2 in Parkinson's disease (7R01NS112506-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10308145. Licensed CC0.

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