# The Function of Synuclein

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $500,983

## Abstract

Signaling in the nervous system depends on the regulated exocytosis of specialized secretory vesicles.
Membrane fusion initiates the process of release, but behavior of the pore formed by fusion can control the rate,
extent and identity of what is released. Indeed, the fusion pore can reseal before full vesicle collapse into the
plasma membrane, potentially trapping unreleased cargo in a form of exocytosis known as `kiss-and-run', a
regulatory mechanism well-established for large dense core vesicles (LDCVs), which release neuromodulators.
However, the mechanisms that regulate behavior of the fusion pore have remained unclear and its role in the
release of classical neurotransmitters from synaptic vesicles (SVs) has been controversial. The actin
cytoskeleton and its associated proteins have been suggested to influence pore behavior but the role has
remained unclear.
 The presynaptic protein α-synuclein has a central role in the pathogenesis of Parkinson's disease (PD).
Human genetics shows that mutations in synuclein can cause the disease and the protein accumulates in all
patients with the idiopathic disorder. Like other proteins important for neurodegeneration, however, its normal
function has remained unknown. Using knockout mice and imaging by light and electron microscopy, we have
found that endogenous synuclein normally regulates the fusion pore formed by both LDCVs and SVs, thus
influencing the mode of release. The long-term objectives of this program are to understand how synuclein
cooperates with other cellular factors to promote fusion pore dilation and how a disturbance in this activity
contributes to disease. Since the available methods have limited analysis of the fusion pore and vesicle collapse,
we have developed new methods to image the full scope of exocytosis by individual vesicles. Using these, we
will study the role of synuclein in pore dilation and membrane collapse by both large dense core vesicles and
synaptic vesicles. Specifically, we propose to
1) Characterize the role of synuclein in exocytosis by imaging at high resolution with several complementary
methods, including false fluorescent neurotransmitters and Alexa dye entry.
2) Assess the interaction of synuclein with the actin cytoskeleton. Observations in multiple systems have
implicated the actin cystoskeleton in exocytosis including pore dilation and we will determine whether synuclein
acts through a common or independent mechanism.
3) Determine how the structure of α-synuclein contributes to its role in exocytosis. We will determine how the N-
terminal repeats and C-terminus contribute to normal function. We will test the role of established
phosphorylation sites since they may contribute to idiopathic disease by mimicking inherited mutations.

## Key facts

- **NIH application ID:** 9855090
- **Project number:** 5R01NS109295-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ROBERT H EDWARDS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,983
- **Award type:** 5
- **Project period:** 2019-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9855090

## Citation

> US National Institutes of Health, RePORTER application 9855090, The Function of Synuclein (5R01NS109295-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9855090. Licensed CC0.

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