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dc.contributor.authorGao, Jianqun
dc.date.accessioned2019-06-06
dc.date.available2019-06-06
dc.date.issued2019-01-18
dc.identifier.urihttp://hdl.handle.net/2123/20502
dc.description.abstractParkinson’s disease (PD) is a progressively debilitating neurodegenerative disorder with the formation and development of Lewy bodies (LBs) and Lewy neurites (LNs) as its pathological characteristics. The most prominent and well-studied component of LBs and LNs is α-synuclein, which is thought to propagate through PD brain and contribute to neural dysfunction and clinical symptoms. The α-synuclein protein invades vulnerable neurons in the PD brain in a predictable, staged pattern. Recent evidence suggests that this propagation has some characteristics similar to the propagation of the prion protein, with distinct toxic α-synuclein species triggering the pathological conversion of normal endogenous α-synuclein in neighboring cells. However, the mechanism by which α-synuclein is taken up, accumulated and transferred within neurons remains to be fully defined. In this study I have used two different models of PD pathology, α-synuclein pre-formed fibrils (PFFs) and TLR2 activation with Pam3CSK4, to induce α-synuclein accumulation in differentiated SH-SY5Y cells and primary induced pluripotent stem cells (IPSCs)-derived neurons. Both cell models resulted in the accumulation of endogenous α-synuclein which peaked at 4-6 days post treatment. Such accumulation was absent in α-synuclein knockout SH-SY5Y cells, indicating the essentiality of endogenous α-synuclein for PD pathology. The PFF- or Pam3CSK4- triggered α-synuclein aggregation was associated with a temporal block in autophagy, as indicated by an increase in the selective autophagy markers p62/SQSTM1, LC3 and LAMP2, suggesting α-synuclein may be increased due to impaired macroautophagy / chaperone-mediated autophagy (CMA) clearance. Moreover, the accumulation of α-synuclein could be ameliorated by promoting autophagy with rapamycin or activators of the 5’ AMP-activated protein kinase (AMPK). TLR2 has recently been suggested as a receptor for endocytosis of α-synuclein. I generated TLR2 KO cells and observed an attenuation of α-synuclein accumulation as well as a suppression of inflammatory responses post Pam3CSK4 treatment in SH-SY5Y cells. Finally, a number of small molecule inhibitors targeting the TLR2 pathway were identified to ameliorate the accumulation of α-synuclein in neural cells, albiet less significantly than the AMPK agonists. These observations increase understanding of the mechanisms involved in PD pathology and provide a convenient model for the screening of potential therapeutics to prevent α-synuclein accumulation. These results suggested that targeting the AKT-mTORC1 and/or TLR2 signaling pathways might be potential therapeutic options for preventing α-synuclein accumulation in PD.en_AU
dc.publisherUniversity of Sydneyen_AU
dc.publisherFaculty of Medicine and Healthen_AU
dc.publisherCentral Clinical Schoolen_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectParkinson's diseaseen_AU
dc.subjectalpha-synucleinen_AU
dc.subjecttoll-like receptor 2en_AU
dc.subjecthuman neuronsen_AU
dc.subjectAMPKen_AU
dc.subjectautophagyen_AU
dc.titleTLR2 and α-synuclein mediated pathology in human neuronal cell modelsen_AU
dc.typePhD Doctorateen_AU
dc.type.pubtypeDoctor of Philosophy Ph.D.en_AU
dc.description.disclaimerAccess is restricted to staff and students of the University of Sydney . UniKey credentials are required. Non university access may be obtained by visiting the University of Sydney Library.en_AU


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