# Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases

> **NIH NIH RF1** · MARINE BIOLOGICAL LABORATORY · 2022 · $1,983,038

## Abstract

PROJECT ABSTRACT
Aggregation of α-synuclein throughout the neuron, including at synapses, is a pathological hallmark of
Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and variants of Alzheimer’s disease (AD).
Synaptic aggregation of α-synuclein is strongly associated with cognitive deficits and dementia in PD
and DLB. The long-term goal of this project is to identify the cellular and molecular mechanisms that
give rise to α-synuclein-induced synaptic deficits and to develop strategies for reversing them. While it
is generally agreed that α-synuclein accumulation at synapses impairs synaptic vesicle trafficking, the
underlying mechanisms remain unclear, preventing the development of treatments for improving
synaptic function in PD and DLB. Over the last decade, we developed and implemented lamprey
reticulospinal synapses as a new model for studying how α-synuclein accumulation impacts synapse
structure and function. Our lab was the first to discover that acutely introducing excess α-synuclein to
synapses, mimicking increased expression in PD and DLB, inhibits synaptic vesicle endocytosis. This
result was subsequently corroborated at mammalian synapses. We then discovered that different
molecular species of α-synuclein (e.g. monomers vs. dimers) cause distinct impacts on endocytosis,
emphasizing the need to understand how each species affects synaptic vesicle trafficking and the
underlying mechanisms. Experiments proposed here will significantly advance the field by: determining
how post-translational modifications of α-synuclein alter its effects at synapses (Aim 1); identifying how
α-synuclein oligomers purified from human PD and DLB brains affect synapses (Aim 2); and examining
the underlying mechanisms with selective inhibitors of α-synuclein membrane binding and
oligomerization (Aim 3). The project is significant because it will substantially increase our
understanding of the impacts of excess α-synuclein on synapses, including pathology-associated
strains, and it will provide initial testing of α-synuclein inhibitors with therapeutic potential while also
probing the molecular mechanisms.

## Key facts

- **NIH application ID:** 10444260
- **Project number:** 2RF1NS078165-12
- **Recipient organization:** MARINE BIOLOGICAL LABORATORY
- **Principal Investigator:** Jennifer Rebecca Morgan
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,983,038
- **Award type:** 2
- **Project period:** 2012-01-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10444260

## Citation

> US National Institutes of Health, RePORTER application 10444260, Mechanisms of Synaptic Dysfunction in Parkinson s and Other Synuclein-Linked Diseases (2RF1NS078165-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10444260. Licensed CC0.

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