Date of Award

2026-05-01

Degree Name

Doctor of Philosophy

Department

Biological Sciences

Advisor(s)

Sukla Roychowdhury

Abstract

Neurodegenerative disorders (NDDs), including Alzheimer's disease (AD), are characterized by progressive neuronal dysfunction, cytoskeletal disruption, and cognitive decline. Although Tau hyperphosphorylation and neurofibrillary tangle (NFT) formation are classical hallmarks of AD, emerging evidence suggests that microtubule (MT) dysfunction may precede and occur independently of Tau pathology. Understanding upstream regulators of MT dynamics is therefore critical for elucidating early mechanisms of neurodegeneration. Previous work from our laboratory demonstrated that G protein βγ (Gβγ) subunits directly interact with tubulin and promote MT assembly. However, the mechanism of Gβγ signaling in neuronal cytoskeletal stability and neurodegeneration remained poorly understood. The present study investigated the role of Gβγ signaling, specifically Gβ1γ2 (GNB1/GNG2), in regulating MT organization, Tau phosphorylation, and neurodegenerative pathways in SHSY5Y neuronal models. Using pharmacological inhibition and a novel Tet-On inducible GNB1/GNG2 overexpression system, this study demonstrates that inhibition of Gβγ signaling with Gallein disrupts neurite architecture, reduces Gβγ-tubulin co-localization, and alters MT organization. Similar cytoskeletal disruption was observed following inhibition of GSK3β with Tideglusib, supporting crosstalk between Gβγ and PI3K/AKT/GSK3β signaling pathways. Interestingly, both Gallein and Tideglusib reduced Tau phosphorylation at serine 396 while simultaneously promoting MT destabilization and neuronal morphological deterioration, suggesting that Tau phosphorylation status alone may not fully explain neurodegenerative mechanisms. Furthermore, Gβγ inhibition promoted Tau aggregation despite reductions in phospho-Tau levels, supporting emerging evidence that Tau aggregation and NFT formation are structurally heterogeneous and may occur independently of classical hyperphosphorylation pathways. Conversely, inducible overexpression of GNB1/GNG2 promoted neurite outgrowth, increased tubulin expression, altered GSK3β phosphorylation, and produced trends toward reduced amyloid-β expression, suggesting neuroprotective functions of Gβγ signaling. Collectively, these findings identify Gβγ signaling as a novel regulator of MT dynamics and neuronal morphology and support a model in which disruption of Gβγ mediated cytoskeletal regulation contributes to neurodegeneration independently of Tau hyperphosphorylation alone. This work establishes GNB1/GNG2 signaling as a potential upstream modulator of MT stability, Tau regulation, and amyloid-associated pathology and highlights Gβγ signaling as a promising therapeutic target for AD and related NDDs.

Language

en

Provenance

Received from ProQuest

File Size

101 p.

File Format

application/pdf

Rights Holder

Diana I. Olivas

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