The investigation of the role of PLCgamma1 in the TrkA dependent degenerative pathway within dorsal root ganglion sensory neurons
department or school: Science, Irving K. Barber Faculty of (Okanagan)
data provider: DSpace
degree campus: UBCO
creator: Lu, Xueying
issued: 2024-08-26T15:02:23Z
issued: 2024
related degree: Master of Science - MSc
degree grantor: University of British Columbia
description: Developmental axon remodeling is an essential process that ensures the proper development and functioning of the nervous system. Dysregulation of this process is associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Tropomyosin receptor kinase A (TrkA) has shown characteristics of a dependence receptor for NGF. However, how TrkA initiates degeneration and the downstream players remain unclear. This thesis aims to determine if PLCγ1 acts downstream of TrkA-dependent axonal degeneration in dorsal root ganglion (DRG) sensory neurons. It is hypothesized that in the absence of NGF, TrkA induced axon degeneration by activating PLCγ1, thereby inducing cytotoxicity. The first chapter of this thesis investigates the role of PLCγ1 in the axonal degeneration of nerve growth factor (NGF) dependent DRG through drug and in the second chapter, a genetic approach is utilized. First, a drug inhibitor, U73122, is employed to inhibit PLC activities. Unexpectedly, U73122 is proven to be an unsuitable inhibitor of PLCγ1 in DRGs. Our results reveal that U73122 induced changes in axon morphology, increases in Ca²⁺ mobilization, disruption of mitochondria outer membrane potential (MOMP), and a significant increase in PLCγ1 phosphorylation in DRGs. Next, a PLCγ1 Cre-Lox mouse model is used to study DRG degeneration in the absence of PLCγ1. Our results determined that PLCγ1 fl/fl DRGs show similar levels of NGF-dependent growth and degeneration as wild-type DRGs, but in the absence of PLCγ1, DRGs show significantly reduced axonal-induced Ca²⁺ mobilization after NGF deprivation. In Chapter 5, TrkAY⁷⁸⁵F knock-in DRGs were generated and characterized. Phosphorylation of TrkA at Y785 allows PLCγ1 to interact, become phosphorylated, and activated. They were shown to possess normal NGF-dependent growth and degeneration. Moreover, they were shown to have defective TrkA Y785 phosphorylation and show reduced Ca²⁺ mobilization …
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/89025
note: The Investigation of the Role of PLCgamma1 in the TrkA Dependent Degenerative Pathway within Dorsal Root Ganglion Sensory Neurons by Xueying Lu B.Sc., The University of British Columbia, 2021 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE COLLEGE OF GRADUATE STUDIES (Biochemistry and Molecular Biology) THE UNIVERISTY OF BRITISH COLUMBIA (Okanagan) August 2024 © Xueying Lu 2024 ii The following individuals certify that they have read, and recommend to the College of Graduate Studies for acceptance, a thesis entitled: The Investigation of the Role of PLCgamma1 in TrkA Dependent Degenerative Pathway in Dorsal Root Ganglion submitted by Xueying Lu in partial fulfillment of the requirements of the degree of Master of Science in Biochemistry and Molecular Biology Dr. Phil A. Barker; Faculty of Science Co-supervisor Dr. Julien Gibon; Faculty of Science Co-supervisor Dr. David Kaplan; Faculty of Medicine Supervisory Committee Member Dr. Sepideh Pakpour; Faculty of Applied Science Supervisory Committee Member Dr. Sean Lawrence; Faculty of Creative and Critical Studies, Language and World Literatures University Examiner Dr. Paul Van Donkelaar; School of Health and Exercise Sciences External Examiner iii Abstract Developmental axon remodeling is an essential process that ensures the proper development and functioning of the nervous system. Dysregulation of this process is associated with neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Tropomyosin receptor kinase A (TrkA) has shown characteristics of a dependence receptor for NGF. However, how TrkA initiates degeneration and the downstream players remain unclear. This thesis aims to determine if PLCγ1 acts downstream of TrkA-dependent axonal degeneration in dorsal root ganglion (DRG) sensory neurons. It is hypothesized that in the absence of NGF, TrkA induced axon degeneration by activating PLCγ1, thereby i…
has type: Thesis/Dissertation
date issued: 2024-11
is shown at: 10.14288/1.0445156
language: eng
degree discipline: Biochemistry and Molecular Biology
provider: Vancouver : University of British Columbia Library
publisher: University of British Columbia
rights: Attribution-NonCommercial-NoDerivatives 4.0 International
rights URI: http://creativecommons.org/licenses/by-nc-nd/4.0/
scholar level: Graduate
contributor: Barker, Philip A.
contributor: Gibon, Julien
type: Text
identifier URI: http://hdl.handle.net/2429/89025