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Role of ubiquitin-specific protease 25 in the pathogenesis of Alzheimer's disease in Down syndrome

University of British Columbia

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 Alzheimer’s 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 Alzheimer’s disease in Down Syndrome. First, we investigated the transcriptional regulation of human USP25 gene. We identified a functional SP1 binding site within its 5’ 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 study investigated the effect of USP25 in the development of AD in DS. It demonstrated for the first time that USP25 overexpression contributes to the development of AD pathology by regulating APP processing, affecting neurogenesis. Our findings indicated that USP25 may serve as a potential pharmacological target for treating AD specifically in DS.

Text

2018-08-20

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/66842

Neuroscience

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/