# The role of VAMP2 in alpha-synuclein function and pathology

> **NIH NIH R01** · UNIVERSITY OF CINCINNATI · 2021 · $390,489

## Abstract

PROJECT SUMMARY
α-Synuclein (α-Syn) is a protein abundantly distributed in presynaptic terminals. α-Syn pathology is linked to
synucleinopathies including Parkinson’s disease (PD) and Lewy body dementia, and α-Syn missense muta-
tions cause early onset PD. Physiologically, α-Syn functions in synaptic transmission via clustering synaptic
vesicles (SVs) and promoting SNARE-complex assembly. This function strongly depends on binding to SVs.
Pathologically, levels of vesicle-associated membrane protein 2 (VAMP2) and functional monomeric α-Syn
simultaneously decrease with increasing duration of dementia, which implies a potential functional link between
VAMP2 and normal monomeric α-Syn. Preliminary data showed VAMP2 interacts with α-Syn to prevent α-Syn
aggregation. The long-term goal of this project is to define and characterize critical protein factors that stabilize
binding of α-Syn on SVs and test their effect on neuron function and α-Syn induced toxicity. The central hy-
pothesis is that VAMP2 stabilizes α-Syn in its functional conformation on SVs to mediate vesicle clustering and
SNARE-complex assembly, and to prevent pathological aggregation. Guided by strong preliminary data, this
hypothesis will be tested in three specific aims: 1) Determine how VAMP2 prevents α-Syn aggregation and
toxicity; 2) Determine α-Syn’s function in SNARE-mediated fusion in vitro; 3) Determine the influence of
VAMP2 on α-Syn’s function and toxicity in vivo. Under the first aim, α-Syn interaction with VAMP2, folding and
oligomerization will be analyzed in solution and on membranes, using NMR, ThioflavinT, CD, FRET and solid-
state nanopore experiments on recombinant α-Syn variants. Under the second aim, the mechanism and kinet-
ics of SNARE-mediated membrane fusion will be analyzed, using single-molecule fusion, vesicle clustering and
NMR experiments on recombinant α-Syn variants. Under the third aim, localization, function, and aggregation
of α-Syn variants will be analyzed, using biochemical and cell biological assays on primary mouse neurons, in
addition to behavioral and pathology readouts in wild-type and heterozygous VAMP2 mice. The study is ex-
pected to show improved function and reduced toxicity of α-Syn with increased SV binding. This research is
significant because it will (1) clarify the importance of SV binding of α-Syn for SNARE-complex assembly and
neuron function, (2) provide novel insights into the function/dysfunction of recently identified PD-mutations of α-
Syn, (3) provide new insights into the molecular mechanism underlying SV-binding of α-Syn by altering VAMP2
levels, and has (4) translational importance for the targeted development of new strategies aimed at preserving
α-Syn’s function via stabilizing its SV-bound pool through elevating VAMP2 levels. Our study is innovative be-
cause it (1) uses a multidisciplinary approach combining biophysical, biochemical, and cell biological ap-
proaches, (2) uses unique single-particle detection assays to s...

## Key facts

- **NIH application ID:** 10179561
- **Project number:** 1R01NS121077-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** Jacqueline Burre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,489
- **Award type:** 1
- **Project period:** 2021-04-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10179561

## Citation

> US National Institutes of Health, RePORTER application 10179561, The role of VAMP2 in alpha-synuclein function and pathology (1R01NS121077-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10179561. Licensed CC0.

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