# An in vivo multiplex model to study gene-environment interaction in Parkinson's Disease > **NIH NIH R00** · UNIVERSITY OF ROCHESTER · 2024 · $249,000 ## 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, respectively, which can modify PD risk. 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, the 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. These experiments will be performed in the laboratory of primary mentor Mel B. Feany. 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. These experiments will be performed in Dr. Feany's lab. In the independent R00 section, a druggable target that can modify the interaction among LRRK2, rotenone, and α-synuclein will be identified. Further, we will screen for other PD-related neurotoxicants that interact with LRRK2 and α-synuclein through actin hyperstabilization. We will genetically and pharmacologically inhibit MRCKα, a kinase that can regulate actin hyperstabilization, in flies, iPSC-derived neurons, and a mouse model. My neurotoxicology and neurodegeneration training will be facilitated by didactic courses and participation in Clinical Pathological conferences at Harvard Medical School and the Exposome boot camp at Columbia University organized by co-mentor Gary Miller. This project may elucidate a novel model system that can be used to identify and study the mechanism of gene-environment ... ## Key facts - **NIH application ID:** 10875466 - **Project number:** 5R00ES033723-03 - **Recipient organization:** UNIVERSITY OF ROCHESTER - **Principal Investigator:** Souvarish Sarkar - **Activity code:** R00 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $249,000 - **Award type:** 5 - **Project period:** 2023-07-01 → 2026-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10875466 ## Citation > US National Institutes of Health, RePORTER application 10875466, An in vivo multiplex model to study gene-environment interaction in Parkinson's Disease (5R00ES033723-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10875466. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*