Role of ubiquitin-specific protease 25 in the pathogenesis of Alzheimer's disease in Down syndrome
department or school: Medicine, Faculty of
data provider: DSpace
degree campus: UBCV
creator: Song, Beibei
issued: 2018-08-20T16:53:25Z
issued: 2018
related degree: Doctor of Philosophy - PhD
degree grantor: University of British Columbia
description: Down syndrome (DS) is the most common genetic cause of intellectual disabilities. Trisomy 21, an extra copy of human chromosome 21, causes the majority of DS cases. After middle age, individuals with DS inevitably develop Alzheimerâs disease, the most common form of neurodegenerative diseases characterized by extracellular amyloid plaque deposition, intracellular neuritic fibrillary tangles and neuronal loss. The extracellular amyloid plaques are made of amyloid β (Aβ) proteins derived from β- and γ- cleavage of amyloid precursor protein (APP). The abnormal accumulation of Aβ proteins plays an essential role in AD pathogenesis. Ubiquitin-specific protease 25 (USP25) is a deubiquitinating enzyme that locates in the DS critical region of human chromosome 21. It is overexpressed in DS patients and has been shown involved in a variety of cellular processes, including immunity, myogenesis and protein degradation. However, the potential role of USP25 in neurodegenerative diseases has not been examined yet. This thesis entails an examination of the role of USP25 in the pathogenesis of Alzheimerâs disease in Down Syndrome. First, we investigated the transcriptional regulation of human USP25 gene. We identified a functional SP1 binding site within its 5â promoter region. We found that Sp1 signaling up-regulated USP25 transcription. Then we showed that USP25 affected APP processing by slowing down the degradation of APP and BACE1. It also altered the intracellular trafficking of BACE1 and promoted C-terminal fragment (CTF) production, indicating its role in amyloidogenic pathway in AD pathogenesis. In the third chapter, we examined the effects of USP25 on neuronal survival and proliferation. We found that USP25 overexpression facilitated oxidative stress-induced cell death and caspase-3 activation through inhibiting NF-κB activation. It upregulation also affects cell cycle regulation both during embryonic neurogenesis and adulthood cortical development. In summary, this…
aggregated CHO: https://circle.library.ubc.ca/rest/handle/2429/66842
note: ROLE OF UBIQUITIN-SPECIFIC PROTEASE 25 IN THE PATHOGENESIS OF ALZHEIMERâS DISEASE IN DOWN SYNDROME by Beibei Song B.Sc., Memorial University, 2013 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENT FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Neuroscience) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2018 © Beibei Song, 2018 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Role of USP25 in the Pathogenesis of Alzheimerâs Disease in Down Syndrome submitted by Beibei Song in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience Examining Committee: Weihong Song Supervisor Yutian Wang Supervisory Committee Member Xin-Ming, Li External Examiner Honglin Luo University Examiner Christian Kastrup University Examiner Additional Supervisory Committee Members: Ann Marie Craig Supervisory Committee Member Jason Snyder Supervisory Committee Member iii Abstract Down syndrome (DS) is the most common genetic cause of intellectual disabilities. Trisomy 21, an extra copy of human chromosome 21, causes the majority of DS cases. After middle age, individuals with DS inevitably develop Alzheimerâs disease, the most common form of neurodegenerative diseases characterized by extracellular amyloid plaque deposition, intracellular neuritic fibrillary tangles and neuronal loss. The extracellular amyloid plaques are made of amyloid β (Aβ) proteins derived from β- and γ- cleavage of amyloid precursor protein (APP). The abnormal accumulation of Aβ proteins plays an essential role in AD pathogenesis. Ubiquitin-specific protease 25 (USP25) is a deubiquitinating enzyme that locates in the DS critical region of human chromosome 21. It is overexpressed in DS patients and has been shown involved in a variety of cellular processes, including immunity, myogenesis and protein…
has type: Thesis/Dissertation
date issued: 2018-09
is shown at: 10.14288/1.0371122
language: eng
degree discipline: Neuroscience
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
type: Text
identifier URI: http://hdl.handle.net/2429/66842