Date of Award

8-2026

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Engineering and Sciences

First Advisor

Melissa A. Borgen

Second Advisor

Timothy A. Crombie

Third Advisor

Jianhui Li

Fourth Advisor

Shaohua Xu

Abstract

Neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, are characterized by the accumulation of pathological tau proteins and progressive neuronal loss. Although research regarding tau-mediated toxicity is extensive, the specific pathology that determine whether neurons maintain homeostasis or succumb to collapse under tau-induced stress remain incompletely elucidated. A central, yet still insufficiently understood, feature of these diseases is the disruption of the microtubule (MT) cytoskeleton . The PHR protein family is evolutionarily highly conserved; within this family, RPM-1 in C. elegans functions as an intracellular signaling hub that regulates axon development, synapse formation, axon termination, and various microtubule-associated processes. This study investigates the roles of RPM-1 and its downstream genes within the context of tauopathy. Utilizing a C. elegans tauopathy model, we demonstrate that the loss of rpm-1 confers a protective effect. We have delineated the complex genetic network through which RPM-1 exerts its influence: RPM-1 promotes neurodegeneration via the downstream effectors GLO-4, while simultaneously inhibiting the neuroprotective DLK-1 mitogen-activated protein kinase (MAPK) cascade, as well as the parallel, pro-degenerative MLK-1 MAPK pathway. Furthermore, we establish a link between this signaling network and microtubule stability. We investigated the impact of disease-associated TauV337M allele on microtubule dynamics; genetic interactions within a ptl-1/Tau background revealed that the loss of the microtubule minus-end binding protein PTRN-1 exerts an unexpected protective effect, suggesting that microtubule stability factors undergo context-dependent regulation during neurodegeneration. Concurrently, in vivo imaging analysis of EBP-2::GFP allowed us to assess the effects of TauV337M on microtubule dynamics. This dissertation establishes RPM-1 as a signaling hub that integrates multiple pathways to govern neuronal survival in tauopathies, acting primarily through the regulation of downstream pathways and a potential role in microtubule integrity, thereby revealing novel potential therapeutic targets.

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