Advisor(s)

Briana De Miranda

Committee Member(s)

Ashley Harms
David Standaert
Rita Cowell
Talene Yacoubian

Document Type

Dissertation

Date of Award

6-16-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Joint Health Sciences

Abstract

Parkinson's disease (PD) is a progressive motor neurodegenerative disorder with a predominantly idiopathic etiology. More recently, however, the contribution of exogenous risk factors such as environmental contaminants has become of interest. Some endogenous genetic risk factors have been well characterized, but the mechanisms by which exogenous insults, such as environmental contaminants, drive dopaminergic neurodegeneration remain incompletely understood. This dissertation will address how environmental contaminants converge on mitochondrial and lysosomal dysfunction to activate parallel neurotoxic signaling pathways, with a focus on the LRRK2 kinase and the cGAS-STING innate immune pathway. Chapter 2 demonstrates that pharmacological inhibition of LRRK2 kinase activity protects against oxidative stress induced by sub-toxic environmental contaminant exposure in a LRRK2-dependent manner, rescues mitophagy deficits, attenuates mitochondrial damage and microglial activation, and confers neuroprotection in a post-lesion in vivo model. Chapter 3 demonstrated that chronic trichloroethylene (TCE) inhalation activated the STING pathway in the substantia nigra prior to detectable neurodegeneration and remained elevated into the neurodegenerative phase. Functional loss of STING was protective against TCE-induced dopaminergic neuron loss and dampened microglial activation, but did not alter baseline rates of mitochondrial damage. This supports the idea that STING mediates the neuroinflammatory response rather than serving as the initiating insult. Chapter 4 characterized the oral microbiome following TCE exposure via oral gavage, recapitulating findings observed in PD patient populations, including reductions in short-chain fatty acid-producing bacteria and increases in opportunistic species, extending the relevance of this environmental model to peripheral pathology. Together, these outcomes shape a model in which environmental toxicants drive co-occurring mitochondrial and lysosomal dysfunction, activating LRRK2 and STING as parallel but ultimately convergent, neurotoxic pathways. The identification of a potential feedforward loop between STING and LRRK2 — wherein STING activates LRRK2 and elevated LRRK2 kinase activity impairs lysosomal STING clearance — reveals a probable self-perpetuating inflammatory mechanism with multiple therapeutic intervention points. These results provide evidence for LRRK2 kinase inhibition and STING pathway blockade as promising neuroprotective strategies in environmentally linked neurotoxicity and neurodegeneration.

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