# Pathophysiologic roles of alpha-synuclein at the synapse

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $48,443

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall goal of this proposal is to clarify mechanistic pathobiological events underlying Lewy body (LB)
dementias – a dementing illness with cognitive impairment that affects more than a million Americans. An
established molecular player in LB dementia is the small presynaptic protein α-synuclein. Amongst a plethora of
incriminating evidence, genomic multiplications and mutations of α-synuclein are seen in families harboring these
diseases; and it has been long recognized that understanding the mechanistic events that lead to α-synuclein-
mediated toxicity in LB dementia is of utmost importance. For over a decade, a primary focus in the field has
been to decipher the normal function of α-synuclein, with the ultimate goal of understanding transition to
pathologic states. However, despite considerable effort, the precise mechanisms underlying the normal function
of α-synuclein, and early triggers leading to pathologic aggregation remain elusive. The basis of our proposal is
a series of pilot experiments, where we uncovered novel roles for two functional partners of α-synuclein, and we
hypothesize that abnormalities in these associations are the initial pathologic triggers for LB dementias. Previous
work from us and others has helped shape a consensus that α-synuclein is a physiologic attenuator of
neurotransmitter release, though underlying mechanistic events are unclear. In these previous studies, we
proposed a model where α-syn organizes into higher-order multimers that physiologically tether synaptic vesicles
(SVs) – leading to a diminution in SV-mobilization, SV-recycling, and consequently, neurotransmitter release. In
new pilot experiments, we discovered novel roles for two other presynaptic proteins – VAMP2 and synapsin – in
helping α-synuclein attenuate neurotransmission. Eventually, our data led us to a working model where synapsin
and VAMP2 play sequential roles in executing α-synuclein function. Tenets of this model will be tested in Aims
1/2. Additionally, an emerging idea in the field is that disruption of physiologic associations might allow free α-
synuclein monomers to aggregate – triggering pathology – and that this might be one of the earliest pathologic
events in disease; however, in vivo evidence is lacking. Leveraging our discoveries on functional α-synuclein
partners, Aims 2/3 will ask if a disruption of these associations might also accelerate pathology in cellular and
animal models of LB dementias. Our aims are: Aim #1: Identify the role of VAMP2 in α-synuclein mediated
synaptic attenuation. Aim #2: Identify the role of synapsin in α-synuclein mediated synaptic attenuation and
pathology. Aim #3: Test the hypothesis that disrupting physiologic associations can trigger α-synuclein
pathology in vivo. Upon completion, our studies should reveal vital clues into the normal function of α-synuclein,
as well as events that trigger dementia and cognitive impairment in these devastating illnesses.

## Key facts

- **NIH application ID:** 10330337
- **Project number:** 3R01NS111978-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Subhojit Roy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $48,443
- **Award type:** 3
- **Project period:** 2021-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10330337

## Citation

> US National Institutes of Health, RePORTER application 10330337, Pathophysiologic roles of alpha-synuclein at the synapse (3R01NS111978-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10330337. Licensed CC0.

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