# Investigating the Role of LRRK2 Hyperactivity in Autophagic and Synaptic Deficits

> **NIH NIH F31** · UNIVERSITY OF PENNSYLVANIA · 2021 · $46,036

## Abstract

PROJECT SUMMARY
 Parkinson’s disease (PD) is the second-most prevalent neurodegenerative disease and the fastest-
growing. PD increases in both prevalence and severity with age, and the disease burden is projected to
dramatically increase in coming decades as the population ages. Current therapies do not address the
underlying neurodegeneration, and development of improved therapeutics is hindered by poor understanding
of the pathogenesis. Changes in homeostatic regulation of both autophagy and synaptic transmission have
been implicated in not only PD but also physiological aging. Leucine-rich repeat kinase 2 (LRRK2) is a leading
candidate for a nexus bridging autophagy and PD pathogenesis. Mutations in LRRK2 are the most common
genetic cause of PD, and increased LRRK2 kinase activity has also been linked to idiopathic PD. There is
accumulating evidence that multiple PD-causative pathways may converge on disrupting autophagy through
mechanisms dependent on LRRK2 activity. Recently, LRRK2 was shown to phosphorylate a subset of Rab
GTPases, providing an important opportunity to make advances in the understanding of mechanisms
downstream of LRRK2. The goal of this proposal is to elucidate the role that LRRK2 may play in autophagy
and synaptic homeostasis, in the context of pathogenic mutations associated with PD. Our preliminary data
suggests that the most common pathogenic mutation in LRRK2, p.G2019S, disrupts autophagic vesicle (AV)
transport in the axons of rodent and iPSC-derived human neurons. We hypothesize that multiple pathogenic
PD mutations disrupt autophagy and synaptic vesicle precursor (SVP) transport through mechanisms
dependent on increased LRRK2 kinase activity. To test this hypothesis, we will exploit iPSC-derived neurons
as a human disease model. Experiments proposed in Aim 1a will explore whether LRRK2-p.G2019S causes
deficits in AV cargo degradation, as a potential mechanism of neurodegeneration. In Aim 1b, we will determine
whether the VPS35-p.D620N mutation, a different pathogenic PD mutation that increases LRRK2 activity,
causes similar autophagy deficits as LRRK2-p.G2019S. Finally, in Aim 2, we will explore whether SVP
transport from the soma to the axon is impaired by mutations causing LRRK2 hyperactivity, with potential
ramifications for synaptic homeostasis. Collectively, we expect that these Aims will help elucidate mechanisms
by which multiple causes of PD can converge on a LRRK2-dependent pathway to disrupt neuronal autophagy
and synaptic homeostasis. Additionally, this work may provide a foundation for future work to shed light on
pathways by which physiological aging alters these processes in the absence of diseases of aging. To
complement this research plan, a comprehensive training plan will help the trainee meet specific Research
Goals, Professional Goals (including writing, mentoring, and presentation), and Clinical Goals (tying together
an integrated physician-scientist training pathway), all in a supportive, col...

## Key facts

- **NIH application ID:** 10313150
- **Project number:** 1F31NS124249-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Dan Dou
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2022-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313150

## Citation

> US National Institutes of Health, RePORTER application 10313150, Investigating the Role of LRRK2 Hyperactivity in Autophagic and Synaptic Deficits (1F31NS124249-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10313150. Licensed CC0.

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