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The role of G protein-coupled Receptor Kinases in tau pathogenesis in Alzheimer’s Disease

Rafael Guimaraes, Thais (2024) The role of G protein-coupled Receptor Kinases in tau pathogenesis in Alzheimer’s Disease. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Alzheimer's Disease (AD) is characterized by pathological aggregation and accumulation of hyperphosphorylated microtubule-associated protein tau in intracellular neurofibrillary tangles (NFTs). There is an undeniable association between the occurrence of tau dysfunction and the onset of cognitive impairment in AD. However, the mechanisms driving and modifying this aggregation process remain elusive. Phosphorylation is a vital cellular process associated with protein homeostasis and disease. Tau, for instance, has 85 putative phosphorylation sites, which regulate both physiological and pathological tau functions. Although several tau kinases have been identified to play causative roles in AD tau pathogenesis, kinase-targeted therapies for AD have been unsuccessful thus far. Interestingly, the kinases responsible for several putative tau phosphorylation sites remain unknown. G protein-coupled receptor (GPCR) kinases (GRKs) are a family of seven kinases (GRKs 1-7) that are implicated in numerous peripheral and brain pathologies. Importantly, GRK signaling is positioned between more than 800 GPCRs and thousands of downstream effectors. Moreover, GRKs have been increasingly appreciated for their roles beyond phosphorylation and regulation of GPCR substrates. Combining the influential role of tau phosphorylation in AD, the high druggability of GPCRs and kinases, and the putative node of intersection that GRK signaling provides, we hypothesize that GRKs orchestrate important aspects of the AD pathogenic cascade. Here, we first established the GRK profile and pattern of expression in the human brain to provide insights into the putative involvement of GRKs in tau pathobiology in AD. We demonstrate that the GRKs differentially associated with neuropathological signatures of tau in AD brains, suggesting that GRKs may regulate tau phosphorylation, solubility, and aggregation in AD. As such, we further elucidate a causal role for GRK2 in tau pathology utilizing a novel optogenetic cellular model of tau aggregation. We also determine an influential role of GRK2 in inducing tau phosphorylation and mediating its degradation. Our findings are further validated in patient-derived neurons, which provides promising translatability for the role of GRK2 in tau pathophysiology. Altogether, we causally implicate GRK2 as a multifactorial modulator of AD pathogenesis and support further investigation of GRK-mediated therapeutic intervention strategies for AD.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Rafael Guimaraes, Thaisthr38@pitt.eduthr380000-0001-8324-0269
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairAizenman, Eliasredox@pitt.edu
Committee MemberHerrup, Karl
Committee MemberSun, Dandan
Committee MemberDonnelly, Christopher
Thesis AdvisorThathiah, Amantha
Committee MemberMertens, Jerome
Date: 27 September 2024
Date Type: Publication
Defense Date: 15 April 2024
Approval Date: 27 September 2024
Submission Date: 30 April 2024
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 286
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurobiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Alzheimer's Disease; Tau; GPCR; Kinase; GRK
Date Deposited: 27 Sep 2024 15:35
Last Modified: 27 Sep 2024 15:35
URI: http://d-scholarship.pitt.edu/id/eprint/46370

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