# Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2021 · $415,625

## 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. Current therapies for PD are palliative but no
disease-modifying therapies exist today. Mutations in the VPS35 (PARK17) gene were recently identified as a
cause of late-onset, autosomal dominant PD, with a single mutation (D620N) detected in PD individuals and
families worldwide. How mutations in VPS35 precipitate dopaminergic neurodegeneration in PD remains
obscure. It is critical to identify the molecular and cellular mechanisms that lead to neurodegeneration due to
VPS35 mutations in order to understand the pathophysiology of PD and develop new therapeutic strategies.
VPS35 is a core component of the retromer complex responsible for the recognition and sorting of
transmembrane protein cargo from endosomes to the Golgi network or plasma membrane for recycling. How
familial mutations influence VPS35 retromer function in PD-relevant neuronal populations and animal models
is not known. We have recently developed a novel viral-mediated gene transfer model of PD in rats where the
overexpression of human D620N VPS35 induces the degeneration of nigrostriatal pathway dopaminergic
neurons, thereby formally establishing a pathogenic role for the D620N mutation in vivo. In the present
application, we now propose to extend our studies to novel D620N VPS35 knockin mice with physiological
levels of VPS35 expression as a new relevant model of VPS35-linked PD (Aim 1). We propose to identify
neurodegenerative phenotypes in the D620N VPS35 knockin mice, including the development and
progression of dopaminergic neuronal and axonal degeneration, striatal catecholamine and motoric deficits,
neuropathology and protein aggregation. We will evaluate abnormal retromer cargo sorting and VPS35 protein
interactions in brain tissue from these mice to identify molecular mechanisms underlying the D620N mutation.
We will also evaluate a novel interaction of VPS35 with α-synuclein and LRRK2 in rodent models of PD to
determine whether these proteins converge in common pathogenic pathways underlying neurodegeneration in
PD (Aims 2-3). We will determine whether VPS35 overexpression or pathogenic mutations can protect or
exacerbate αSyn-dependent neurodegeneration, respectively, in two well-characterized rodent models of PD
(Aim 2). We will also provide evidence of whether familial LRRK2 mutations act to induce a retromer deficiency
in the brain using two distinct LRRK2 rodent models of PD, and we will evaluate whether VPS35 mutations or
deficiency in mice can exacerbate mutant LRRK2-induced dopaminergic neurodegeneration (Aim 3). Our
comprehensive proposal is novel, innovative and timely and will provide important insight into the pathogenic
actions and mechanisms of VPS35 mutations in PD by using a novel knockin mouse model.

## Key facts

- **NIH application ID:** 10227170
- **Project number:** 5R01NS105432-05
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Darren John Moore
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $415,625
- **Award type:** 5
- **Project period:** 2017-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227170

## Citation

> US National Institutes of Health, RePORTER application 10227170, Mechanisms of VPS35-Dependent Neurodegeneration in Parkinson's Disease (5R01NS105432-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10227170. Licensed CC0.

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