Date of Award

2026-05-01

Degree Name

Doctor of Philosophy

Department

Environmental Sciences

Advisor(s)

Mahesh Narayan

Abstract

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental contaminants with widespread human exposure and well-established links to adverse health outcomes. However, despite increasing epidemiological and experimental evidence, the molecular mechanisms underlying PFAS-induced neurotoxicity remain incompletely defined. This dissertation investigates PFAS toxicity across biological scales, integrating protein biophysics with neuronal cell models to elucidate pathways relevant to neurodegeneration. At the molecular level, we demonstrate that PFAS disrupts the structure and function of globular proteins, including the impairment of α-lactalbumin's calcium-binding capacity and of β-lactoglobulin's retinol binding, through concentration-dependent conformational destabilization. By applying these findings to a neuronal model, we show that multiple PFAS congeners (PFOA, PFOS, PFDA, PFNA) induce proteostasis disruption, promote α-synuclein aggregation, and increase phosphorylation at Ser129 (pS129) in differentiated SH-SY5Y dopaminergic models. These effects occur alongside reduced neurite outgrowth and impaired mitochondrial function, with increased susceptibility observed in the A53T α-synuclein SNCA mutation, supporting a neural exposome framework. Collectively, these findings identify PFAS as environmental disruptors capable of targeting protein structure and organelle function, leading to convergent proteotoxic and bioenergetic stress pathways. This work provides mechanistic evidence linking PFAS exposure to Parkinson's disease-relevant cellular pathology and begins to establish a molecular basis for evaluating environmental toxicants for neurodegenerative risk.

Language

en

Provenance

Received from ProQuest

File Size

132 p.

File Format

application/pdf

Rights Holder

Daisy Lee Wilson

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