Author ORCID Identifier

https://orcid.org/0000-0001-7636-6656

Date of Award

Fall 8-12-2026

Document Type

Thesis (Ph.D.)

Department or Program

Molecular and Systems Biology

First Advisor

Matthew C. Havrda

Abstract

Neuroinflammation, particularly NLRP3 inflammasome activation, has been implicated in Parkinson's disease (PD) neurodegeneration, but the cell-type-specific contributions of NLRP3 activity remain poorly understood. This dissertation tested whether NLRP3 activation in microglia versus peripherally derived myeloid cells differentially drives Parkinsonian pathology. Microglial NLRP3 gain-of-function was achieved using Nlrp3L351P crossed with Tmem119-CreER, both on an Nlrp3⁻/⁻background. For peripheral myeloid cells, an analogous Ms4a3-Cre-driven strategy resulted in perinatal lethality of animals with Nlrp3L351P restricted to granulocyte-monocyte progenitors (GMPs). Instead, we used Ms4a3-Cre tdTomato reporter mice generated on wild-type and Nlrp3⁻/⁻backgrounds to fate-map GMP-derived myeloid cells and assess their infiltration into the brain following systemic rotenone challenge. Neurodegeneration, oxidative stress, and myeloid activation were assessed via flow cytometry, histology, and multiplex cytokine analysis. Microglia-restricted NLRP3 mice did not reproduce hallmark Parkinsonian pathology, indicating this compartment alone is insufficient to drive neurodegeneration. tdTomato-tagged GMP-derived cells showed NLRP3-dependent oxidative stress at Day 14 and sustained CD16/32⁺ activation at Day 30, suggesting a candidate neuroinvasive phenotype. The perinatal lethality observed in Ms4a3-Cre, Nlrp3L351P animals additionally revealed an essential developmental role for NLRP3 activity in this lineage. These findings indicate NLRP3 activation is not uniformly pathogenic across myeloid compartments in PD, and identify peripheral, GMP-derived myeloid NLRP3 signaling as a key locus warranting further mechanistic and translational investigation.

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