# Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease

> **NIH NIH R35** · FLORIDA INTERNATIONAL UNIVERSITY · 2020 · $823,801

## Abstract

Project Summary
The long term goal of our laboratory is to study the pathogenic mechanisms induced by
environmental toxicants, genetic mutations and gene-environment interactions in Parkinson’s
disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain
disorder. Overall, our research projects address the following fundamental questions: 1) Gene-
environment interactions: Do mutations linked to PD render dopamine neurons more susceptible
to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the
vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been
demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion
be targeted for PD treatment? These research projects have been supported by NIEHS since
2006. This R35 proposal will be built upon the strength, expertise, experimental models and other
resources generated from the NIEHS funded projects in our laboratory to take our work to the
next transformative level. The primary goal of this R35 proposal is to demonstrate that
neurotoxicity induced by neurotoxicants such as manganese (Mn) alone or in combination with
other factors (α-synuclein and gastric bacteria) linked to PD can be mitigated by reducing the
function of dynamin related protein-1 (Drp1), which is typically known as a mitochondrial fission
protein. However, our recent findings have led us to unexpected and exciting mechanism of Drp1
through autophagy. Combined with our recent discoveries that neurotoxicants such as Mn and
paraquat impair autophagy at a low and sub-lethal concentration, our vision is that Drp1 plays a
central role in pathogenic mechanism and this protein can be targeted for PD therapy. Over the
next eight years, this R35 will give us the flexibility and power to fully investigate the extensive
involvement of Drp1 in neurotoxicity mediated by glia-neuron interactions, gene-environment
interactions and gastric bacteria that have been linked to PD. This proposal utilizes a
transdisciplinary approach from a team of accomplished investigators with relevant established
track-records, a wide range of chemical and genetic tools, high standard techniques and
innovative experimental models for molecular target manipulations with functional studies at
cellular, circuit and whole animal levels. Completion of this project will provide paradigm shifts in
our understanding of how Drp1 mediates neurotoxicity through a wide range of toxic insults.

## Key facts

- **NIH application ID:** 9929600
- **Project number:** 5R35ES030523-02
- **Recipient organization:** FLORIDA INTERNATIONAL UNIVERSITY
- **Principal Investigator:** KIM TIEU
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $823,801
- **Award type:** 5
- **Project period:** 2019-06-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9929600

## Citation

> US National Institutes of Health, RePORTER application 9929600, Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease (5R35ES030523-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9929600. Licensed CC0.

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