# Enteric Neuronal Aggregation of a-synuclein causes disruption in Colonic Neurotransmission and results in Colonic Dysmotility

> **NIH NIH F30** · MICHIGAN STATE UNIVERSITY · 2021 · $46,274

## Abstract

Abstract
Gastrointestinal (GI) complications are a significant clinical and economic burden in patients with Parkinson’s
disease (PD). Specifically, constipation is responsible for the most drastic decrease in the quality of life for 24-
63% of PD patients. Yet, due to the lack of knowledge of the mechanisms underlying this symptom, there
haven’t been successful or long-term therapies. It has been well established that aggregated forms of α-
synuclein (α-syn), a presynaptic terminal protein identified to be the pathological marker in PD, is observed
diversely through the enteric nervous system (ENS) of the GI tract in PD patients. α-syn aggregation within the
ENS as well as constipation precede the motor deficits in PD by up to 20 years. Whether this protein is
interfering with neurotransmission in the ENS is currently unknown. Our preliminary data in recombinant
adeno-associated virus with A53T point mutation targeted to enteric neurons in the mouse model found
reduced colonic propulsion suggesting that α-syn maybe disrupting cholinergic neurotransmission. The long-
term objective of this project is to determine whether α-syn aggregation in the colonic myenteric
plexus impairs ENS cholinergic neuromuscular and synaptic transmission causing abnormal colonic
propulsion. To achieve this project objective, Aim 1 will determine the expression of ectopic α-syn in the
myenteric neurons of the colon as this will provide us mechanistic data on the potential interactions between
the protein and neurotransmitter systems. In Aim 2 we will use in vivo and ex vivo paradigms to determine
whether α-syn overexpression disrupts propulsive colonic motility by addressing colonic propulsion and colonic
contractions and relaxations. Aim 3 will use optogenetics to identify the effect of α-syn overexpression on
cholinergic synaptic and neuromuscular transmission in the myenteric plexus. This proposed research will be
the first to directly study cholinergic neurotransmission within the ENS in the presence of α-syn aggregates.
Moreover, we aim to identify novel targets that may initiate new drug discoveries in treating constipation
involved in PD.

## Key facts

- **NIH application ID:** 10168433
- **Project number:** 5F30DK124987-02
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Narayana Krishna Yelleswarapu
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,274
- **Award type:** 5
- **Project period:** 2020-05-16 → 2024-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10168433

## Citation

> US National Institutes of Health, RePORTER application 10168433, Enteric Neuronal Aggregation of a-synuclein causes disruption in Colonic Neurotransmission and results in Colonic Dysmotility (5F30DK124987-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10168433. Licensed CC0.

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