# An in vivo multiplex model to study gene-environment interaction in Parkinson's Disease

> **NIH NIH R00** · UNIVERSITY OF ROCHESTER · 2024 · $62,767

## Abstract

Project Summary/Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by α-synuclein-rich
neuronal inclusions. Recent genome-wide associated studies (GWAS) and epidemiological studies have
identified multiple candidate genes and environmental factors which can modify PD risk. However, studying
polygenic interactions with environmental factors has been difficult due to the lack of a model system. However,
studies have hinted at a complex relationship between α-synuclein, genetic risk factors, and environmental
factors. In our preliminary data, we have established a multiplex model using the Drosophila model of PD. In this
model, we express human α-synuclein, simultaneously modify GWAS candidate genes in neurons, and expose
adult flies to rotenone. Using a combination of scalable techniques in this model, we identified novel interactions
among α-synuclein, environmental factors, and GWAS genes. The overarching hypothesis is a multiplex
model, in combination with iPSC-derived neurons, can be used to identify and study the mechanism of
novel gene-environment interactions. Further, this model system will identify potential drug targets that
can modify the gene-environment interactions.
In Aim 1, a series of experiments, including super-resolution microscopy and iPSC-derived tyrosine hydroxylase
(TH) neurons, will be performed to characterize the interaction among LRRK2, rotenone, and α-synuclein, which
was identified using the multiplex model. Aim 2 will involve understanding the mechanism of interactions among
LRRK2, rotenone, and α-synuclein. Previous studies and preliminary experiments have shown that actin
hyperstabilization plays a central role in regulating neurotoxicity. Herein biochemical, immunohistological, and
neurotoxicity assays will be performed in Drosophila and iPSC-derived TH neurons (obtained disease-causing
LRRK2-G2019S and protective LRRK2-R1398H iPSCs) to study the role of actin dynamics in regulating this
gene-environment interaction. Aim III will identify a druggable target that can modify the interaction among
LRRK2, rotenone, and α-synuclein. Further, we will screen for other PD-related neurotoxicants that interact with
LRRK2 and α-synuclein through actin hyperstabilization. Finally, we will genetically and pharmacologically inhibit
MRCKα, a kinase that can regulate actin hyperstabilization, in flies, iPSC-derived neurons, and a mouse model.
This project may elucidate a novel model system that can be used to identify and study the mechanism of gene-
environment interactions. My training during the K99 phase enabled me to transition to an independent position
at URMC. I will lead a laboratory investigating the molecular mechanisms of gene-environment interactions in
neurodegenerative disorders.

## Key facts

- **NIH application ID:** 11099376
- **Project number:** 3R00ES033723-03S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Souvarish Sarkar
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $62,767
- **Award type:** 3
- **Project period:** 2023-07-01 → 2025-06-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099376

## Citation

> US National Institutes of Health, RePORTER application 11099376, An in vivo multiplex model to study gene-environment interaction in Parkinson's Disease (3R00ES033723-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11099376. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*