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Abnormal Tau Interactions in Neurodegenerative Disease

Hurtle, Bryan (2024) Abnormal Tau Interactions in Neurodegenerative Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Many neurodegenerative disease-related proteins, including Tau and TDP-43, self-assemble into diverse polymeric structures and liquid-like protein phases. These protein phases can organize functionally related proteins, nucleic acids, and biomolecules. These dynamic biomolecular phase transitions give rise to various multicomponent coexisting phases with varying material states known as biomolecular condensates. The most common form of dementia, Alzheimer's disease (AD), as well as >20 other dementias, termed tauopathies, are pathologically defined by insoluble aggregates of the microtubule-associated protein tau (MAPT). Tauopathies represent a wide range of distinct neurodegenerative diseases that display altered expression, mislocalization, and tau protein aggregation as prominent neuropathological features. Although tau aggregation correlates well with AD symptomology, the specific tau species, i.e., monomers, soluble oligomers, and insoluble aggregates that induce neurotoxicity, are incompletely understood. Chapter 2 of this dissertation aims to address some of these questions and overcome the traditional challenges of modeling cellular Tau phase transitions. We develop an optogenetic system (optoTau) that allows light-selective induction of wild-type tau aggregation in cells. Specifically, we created a light-responsive tau protein (optoTAU) and used viscosity-sensitive AggFluor probes to investigate tau aggregation's consequence(s) in human neurons. Furthermore, we also provide proof-of-concept for optoTAU as a pharmacological platform to identify modifiers of tau aggregation.
RNA dysregulation has emerged as a potential mechanism mediating tau-driven neurodegeneration. In Chapter 3, we aim to expand on current knowledge regarding abnormal Tau and RNA-binding protein (RBP) interactions, specifically Tau and TDP-43. Dysfunctional RNA metabolism associated with a loss of TDP-43 function is considered central to amyotrophic lateral sclerosis (ALS) pathogenesis. Interestingly, hallmarks of TDP-43 pathology are observed to be associated with Tau pathology in diseases including Alzheimer's disease (AD), frontotemporal dementia (FTD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). However, a potential pathologic interplay between Tau and TDP-43 and how Tau may mediate RNA dysregulation across these diseases are poorly understood. Alterations in the abundance, localization, and condensation of protein/RNA complexes, or biomolecular condensates, have been shown to modulate the activity of RBPs, including TDP-43. Therefore, we hypothesized that Tau may act as a modifier of TDP-43 localization, protein interaction networks, and function and thus explored potential cellular mechanisms linking Tau and TDP-43.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Hurtle, Bryanbth21@pitt.eduhurtlebt0000-0002-5446-456X
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairSweet, Robertsweet@pitt.edu
Committee MemberBurton, Edwardeab25@pitt.edu
Committee MemberHerrup, KarlHERRUP@pitt.edu
Committee MemberBrodsky, Jeffreyjbrodsky@pitt.edu
Committee MemberCohen, Toddtoddcohen@neurology.unc.edu
Thesis AdvisorDonnelly, Christophercjdon25@pitt.edu
Date: 14 October 2024
Date Type: Publication
Defense Date: 16 May 2024
Approval Date: 14 October 2024
Submission Date: 20 July 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 271
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Protein Phase Transitions, Tau, TDP-43, Neurodegeneration, Protein Aggregation, RNA homeostasis, Therapy development, optogenetics
Date Deposited: 14 Oct 2024 15:01
Last Modified: 14 Oct 2024 15:01
URI: http://d-scholarship.pitt.edu/id/eprint/46707

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