# The Interaction of parkin and environmental toxins in Parkinson’s disease

> **NIH VA I01** · VA WESTERN NEW YORK HEALTHCARE SYSTEM · 2020 · —

## Abstract

Abstract
 Many environmental and genetic factors underlie the degeneration of nigral DA neurons in Parkinson's
disease (PD). Exposure to pesticides such as rotenone and organochlorine herbicides such as 2,4-D, a major
component of Agent Orange used in Vietnam War, has been linked to higher incidence of PD. Nigral DA
neurons have massive axon arborization and are particularly vulnerable to microtubule-depolymerizing agents.
Previous studies show that many environmental PD toxins impact on microtubules. Our previous studies in
vitro and in rat neuronal cultures have shown that parkin binds to and stabilizes microtubules. In our
preliminary studies using iPSC-derived midbrain DA neurons from normal subjects and PD patients with parkin
mutations, we found that parkin mutations markedly reduced the total length and complexity of neuronal
processes by destabilizing microtubules. Furthermore, environmental PD toxins, such as 2,4-D, had much
higher toxicity on midbrain DA neurons from PD patients with parkin mutations than those from normal
controls. To demonstrate that these phenotypes are indeed caused by parkin, we will generate isogenic iPSC
by repairing parkin mutations in PD patient iPSCs and by introducing PD-causing parkin mutations in control
iPSCs. These lines of isogenic iPSCs will be used to examine the impact of PD environmental toxins on human
midbrain DA neurons in vitro and in rat brains. The proposal aims to study how parkin and environmental PD
toxins impact on a common molecular target – microtubules – to affect the survival of midbrain dopaminergic
neurons derived from isogenic pairs of iPSCs. The unique morphology of a single human nigral DA neuron,
with its estimated 4.6 meter long axon arborization, renders the cell particularly vulnerable to genetic (e.g.
parkin mutations) or environmental factors (e.g. rotenone, 2,4-D) that destabilize microtubules. Mechanistic
insights gained from the study on the protective effects of parkin would be useful for the identification of
disease-modifying therapies for PD.

## Key facts

- **NIH application ID:** 9898312
- **Project number:** 5I01BX003831-03
- **Recipient organization:** VA WESTERN NEW YORK HEALTHCARE SYSTEM
- **Principal Investigator:** JIAN FENG
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898312

## Citation

> US National Institutes of Health, RePORTER application 9898312, The Interaction of parkin and environmental toxins in Parkinson’s disease (5I01BX003831-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9898312. Licensed CC0.

---

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