Advisor(s)

Talene Yacoubian
Briana De Miranda

Committee Member(s)

Ashley Harms
David Standaert
Laura Volpicelli-Daley

Document Type

Dissertation

Date of Award

6-18-2026

Degree Name

Doctor of Philosophy (PhD)

School

Joint Health Sciences (Interdisciplinary)

Department

Neurobiology

Abstract

ABSTRACT This dissertation examines how 14-3-3 proteins, with a focus on the 14-3-3θ iso-form, regulate signaling pathways relevant to neurodegeneration. While tradition-ally described as molecular hubs that organize protein–protein interactions, our work reveals how 14-3-3 function is shaped by environmental insults, namely bac-terial and neurotoxicant exposures, and how its disruption contributes to disease-associated processes. Two complementary approaches were used, focusing on microglial inflammatory signaling and neuronal responses to an environmental neurotoxicant, to define a broader role for 14-3-3 proteins in disease associated pathways in the brain. Chapter I identifies 14-3-3 proteins as modulators of microglial activation. Disrup-tion of 14-3-3 interactions enhances NF-κB–dependent signaling, leading to in-creased expression of proinflammatory markers, cytokine production, lysosomal proteolysis, and phagocytic activity, while also impairing migration. These findings support a model in which 14-3-3 proteins constrain inflammatory signaling while coordinating distinct aspects of microglial behavior. Chapter II extends these findings to an environmental context by examining the effects of trichloroethylene exposure. Across multiple experimental models, TCE induces consistent changes in both total 14-3-3θ and its phosphorylation at serine 232, with patterns that vary by time and experimental system. These results sug-gest dysregulation of 14-3-3θ as an early feature of the cellular stress response to TCE. Functional studies show that altering 14-3-3θ expression or phosphorylation does not affect acute oxidative stress to the metabolite trichloroacetic acid (TCA), indicating that its role potentially lies in downstream signaling pathways that are likely associated with mitochondrial dysfunction. Together, these studies position 14-3-3 proteins as a context-dependent regulator within both neuroinflammation and environmental stress. Our findings build on the existing scientific knowledge to better understand how dysregulation of 14-3-3 proteins may contribute to neurodegenerative disease. Keywords: 14-3-3 proteins, microglia, neuroinflammation, , trichloroacetic acid tri-chloroethylene

Keywords

14-3-3 proteins;microglia;neuroinflammation;trichloroacetic acid;trichloroethylene

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