# Mechanisms of synaptic dysfunction in Parkinson's and other synuclein-linked diseases

> **NIH NIH R01** · MARINE BIOLOGICAL LABORATORY · 2021 · $501,073

## Abstract

The long term goal of this project is to identify the cellular and molecular mechanisms that give rise to
the synaptic defects in Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of
Alzheimer’s disease (AD) and to develop strategies for reversing them. A pathological hallmark of
these diseases is aggregation of α-synuclein throughout the neuron, including synapses. The synaptic
aggregation of α-synuclein is thought to be the cause of the cognitive deficits and dementia. While it is
generally agreed that α-synuclein accumulation at synapses impairs vesicle endocytosis, the
underlying mechanisms remain unclear. Thus, at present, there are no known strategies for improving
synaptic function in PD, DLB or AD because we don’t know the cellular or molecular targets. The
proposed experiments take significant steps toward these goals by taking advantage of two classical
vertebrate synapses that are ideally suited for studies on synaptic vesicle trafficking and by using both
acute and genetic perturbations of α-synuclein. The approach includes a combination of quantitative
biochemical, electrophysiological, and imaging assays. One model for α-synuclein toxicity suggests
that it is initiated by formation of abnormal oligomers, while another proposes that build up of
monomers is the trigger. Aim 1 will test predictions of both models at synapses by identifying how
defined molecular species of α-synuclein (monomers, dimers, higher molecular weight oligomers) affect
vesicle trafficking and neurotransmission and the underlying mechanisms. Preliminary studies indicate
that monomers and dimers produce distinct effects. Experiments in Aim 2 will determine the role for α-
synuclein self-association in producing synaptic defects by testing reagents that interfere with this
process, including a drug with potential therapeutic value. Aim 3 is focused on reversing the synaptic
defects caused by excess α-synuclein by perturbing its association with Hsc70 chaperone protein, an
idea that is supported by preliminary data. The experiments are innovative because they are the first to
test the effects of defined molecular species of α-synuclein at synapses, they continue the development
of a new model synapse for these studies, and they will test several new reagents with potential for
ameliorating the synaptic defects. The experiments are significant because they will elucidate the
mechanisms by which excess α-synuclein causes synaptic deficits, and they will provide possible
targeted, molecular strategies for improving synaptic function. Thus, these studies have direct
implications for slowing or halting the neurodegeneration, cognitive deficits, and dementia in PD, DLB
and other related diseases.

## Key facts

- **NIH application ID:** 10166962
- **Project number:** 5R01NS078165-11
- **Recipient organization:** MARINE BIOLOGICAL LABORATORY
- **Principal Investigator:** Jennifer Rebecca Morgan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $501,073
- **Award type:** 5
- **Project period:** 2012-01-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166962

## Citation

> US National Institutes of Health, RePORTER application 10166962, Mechanisms of synaptic dysfunction in Parkinson's and other synuclein-linked diseases (5R01NS078165-11). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10166962. Licensed CC0.

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