# Mechanisms of pesticide-induced neuroinflammation and parkinsonism in aging mice.

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2022 · $418,051

## Abstract

PROJECT SUMMARY
 Complex gene-environment interactions underlie the incidence and progression of Parkinson’s disease (PD).
Our work in pesticide-exposed mice and PD patients indicates that cellular stress associated with environmental
toxicant exposure activates the intracellular inflammasomes. Inflammasomes are intracellular multi-protein
complexes containing pattern recognition receptors that initiate and propagate inflammation. Inflammasomes
have emerged as key mediators of inflammation in neurodegenerative diseases in part because they can sense
non-microbial “sterile” inflammatory triggers commonly observed in chronic, age-related disorders like PD.
Inflammasome triggers identified in models of PD include pesticides, heavy metals, mitochondrial and oxidative
stress, and proteinaceous insults like misfolded synuclein. Our original aims determined that long-term exposure
to the PD-associated pesticide rotenone activated the NLRP3-inflammasome and that Nlrp3-/- mice were
protected from rotenone-induced nigral cell loss. In parallel studies, we identified elevated NLRP3 expression in
degenerating mesencephalic tissues and plasma in PD patients compared with healthy volunteers. These
findings and rapidly advancing efforts to target NLRP3 in the clinic provide a compelling backdrop for continued
analysis of the activities of the NLRP3-inflammasome in the central nervous system. We propose to extend our
studies based on our findings of both microglial and neuronal origins for NLRP3-inflammasome activity and the
concept that plasma borne inflammasome-related proteins may be a novel class of biomarkers for toxicant
exposure and PD. We’ve developed innovative mouse models based on CRE-driven dopamine neuron and
microglial specific Nlrp3 gain-of function. We will utilize our established rotenone exposure model to dissect the
contributions of cell-type specific NLRP3 inflammasome activity to neuroinflammation and nigral
neurodegeneration. In a second aim, we will work to understand the cellular mechanisms that underlie our
detection of plasma-borne inflammasome related proteins in PD patient plasma. These studies will validate LC-
MS/MS studies in which we identified Nlrp3-dependent release of the exocytosis mediators Bruton’s Kinase
(BTK) and Coronin1A (CORO1A). We propose systematic NLRP3, BTK, and CORO1A gain-and-loss of function
studies in genetically modified pesticide-exposed microglial, neuronal, and monocytic cell lines to characterize
novel secretory mechanisms and define brain-cell-type specific NLRP3-dependent secretomes. Studies will
provide mechanistic data and define molecules secreted specifically by distressed brain cells providing a
foundation for the development of diagnostic tools to detect, stratify, and monitor PD. Our study is important
because we work to combat the rapidly increasing global burden of age-related neurodegenerative disorders by
characterizing a pathway common to multiple diseases that can be targeted with already ex...

## Key facts

- **NIH application ID:** 10375629
- **Project number:** 2R01ES024745-06A1
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Matthew Charles Havrda
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $418,051
- **Award type:** 2
- **Project period:** 2022-02-09 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375629

## Citation

> US National Institutes of Health, RePORTER application 10375629, Mechanisms of pesticide-induced neuroinflammation and parkinsonism in aging mice. (2R01ES024745-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10375629. Licensed CC0.

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