{"id":{"repo_id":"unsw","oai_identifier":"oai:unsworks.library.unsw.edu.au:1959.4/53091"},"canonical_url":"https://search.dev.ndltd.org/etd/unsw/oai:unsworks.library.unsw.edu.au:1959.4/53091","repository":{"repo_id":"unsw","name":"University of New South Wales","base_url":"https://unsworks.unsw.edu.au/oai/provider"},"display":{"title":"α-Synuclein phosphorylation and related kinases in Parkinson’s disease","abstract":"Parkinson's disease (PD) is the most common neurodegenerative movement disorder pathologically identified by degeneration of the nigrostriatal system and the presence of Lewy bodies (LBs) and neurites, structural pathologies largely made from insoluble α-synuclein phosphorylated at serine 129 (S129P). Several kinases have been suggested to facilitate α-synuclein phosphorylation in PD, but without significant human data the changes that precipitate such pathology remain conjecture. The major aims of this project were to assess the dynamic changes of α-synuclein phosphorylation and related kinases in the progression of PD and in animal models of PD, and to determine whether Tenuigenin (TEN), a Chinese medicinal herb, can prevent α-synuclein-induced toxicity in a cell model. The levels of non-phosphorylated α-synuclein decreased over the course of PD, becoming increasingly phosphorylated and insoluble. There was a dramatic increase in phosphorylated α-synuclein that preceded LB formation. Importantly, three α-synuclein-related kinases [polo-like kinase 2 (PLK2), leucine-rich repeat kinase 2 (LRRK2) and cyclin G-associated kinase (GAK)] were found to be involved at different times in the evolution of LB formation in PD. Analysis of a subacute MPTP model of PD neurodegeneration revealed similar increases in S129P α-synuclein and PLK2/3 levels occurred immediately after the toxic insult, revealing this in vivo model as suitable to assess this molecular mechanism. Assessment of α-synuclein over-expressing cell models of PD cytotoxicity revealed increased S129P α-synuclein but no increase in PLK2/3 levels, however treatment of these cells with the Chinese herbal extract TEN was effective in reducing the increased S129P α-synuclein and cell toxicity in association with reducing levels of PLK3. This suggests that TEN may be an effective treatment for S129P α-synuclein induced cytotoxicity as observed in PD. In summary, these studies indicate that an increase in S129P α-synuclein occurs early in response to cell damage in both PD and toxin-induced PD models and that the levels of PLK2/3 increase in concert. Human data suggests that different kinases play a precipitating role in LB formation and compaction. Importantly TEN treatment appears to reduce PLK3 levels and ameliorate S129P α-synuclein toxicity, identifying this herbal extract as a potential therapeutic drug for this PD relevant mechanism.","abstract_html":"Parkinson's disease (PD) is the most common neurodegenerative movement disorder pathologically identified by degeneration of the nigrostriatal system and the presence of Lewy bodies (LBs) and neurites, structural pathologies largely made from insoluble α-synuclein phosphorylated at serine 129 (S129P). Several kinases have been suggested to facilitate α-synuclein phosphorylation in PD, but without significant human data the changes that precipitate such pathology remain conjecture. The major aims of this project were to assess the dynamic changes of α-synuclein phosphorylation and related kinases in the progression of PD and in animal models of PD, and to determine whether Tenuigenin (TEN), a Chinese medicinal herb, can prevent α-synuclein-induced toxicity in a cell model. The levels of non-phosphorylated α-synuclein decreased over the course of PD, becoming increasingly phosphorylated and insoluble. There was a dramatic increase in phosphorylated α-synuclein that preceded LB formation. Importantly, three α-synuclein-related kinases [polo-like kinase 2 (PLK2), leucine-rich repeat kinase 2 (LRRK2) and cyclin G-associated kinase (GAK)] were found to be involved at different times in the evolution of LB formation in PD. Analysis of a subacute MPTP model of PD neurodegeneration revealed similar increases in S129P α-synuclein and PLK2/3 levels occurred immediately after the toxic insult, revealing this in vivo model as suitable to assess this molecular mechanism. Assessment of α-synuclein over-expressing cell models of PD cytotoxicity revealed increased S129P α-synuclein but no increase in PLK2/3 levels, however treatment of these cells with the Chinese herbal extract TEN was effective in reducing the increased S129P α-synuclein and cell toxicity in association with reducing levels of PLK3. This suggests that TEN may be an effective treatment for S129P α-synuclein induced cytotoxicity as observed in PD. In summary, these studies indicate that an increase in S129P α-synuclein occurs early in response to cell damage in both PD and toxin-induced PD models and that the levels of PLK2/3 increase in concert. Human data suggests that different kinases play a precipitating role in LB formation and compaction. Importantly TEN treatment appears to reduce PLK3 levels and ameliorate S129P α-synuclein toxicity, identifying this herbal extract as a potential therapeutic drug for this PD relevant mechanism.","abstract_has_math":false,"creators":["Zhou, Jin-Xia"],"institution":"UNSW, Sydney","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2013,"date_issued":"2013","date_published":"2013","updated_at":"2026-07-24T05:33:55Z","subjects":["Kinases","α-synuclein","Phosphorylation","Parkinson’s disease"],"languages":["EN"],"rights":["open access","CC BY-NC-ND 3.0","free_to_read"],"rights_urls":["https://purl.org/coar/access_right/c_abf2","https://creativecommons.org/licenses/by-nc-nd/3.0/au/"],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.26190/unsworks/16526"],"render_values":[{"text":"https://doi.org/10.26190/unsworks/16526","href":"https://doi.org/10.26190/unsworks/16526","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/1959.4/53091","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Zhou, Jin-Xia"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2013"]},{"key":"dc:publisher","label":"Institution","values":["UNSW, Sydney"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Kinases","α-synuclein","Phosphorylation","Parkinson’s disease"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["EN"]},{"key":"dc:rights","label":"Dc Rights","values":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/1959.4/53091","https://unsworks.unsw.edu.au/bitstreams/fa6bcc8e-6c2b-476f-a147-d2e0449541cf/download","https://doi.org/10.26190/unsworks/16526"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Parkinson's disease (PD) is the most common neurodegenerative movement disorder pathologically identified by degeneration of the nigrostriatal system and the presence of Lewy bodies (LBs) and neurites, structural pathologies largely made from insoluble α-synuclein phosphorylated at serine 129 (S129P). Several kinases have been suggested to facilitate α-synuclein phosphorylation in PD, but without significant human data the changes that precipitate such pathology remain conjecture. The major aims of this project were to assess the dynamic changes of α-synuclein phosphorylation and related kinases in the progression of PD and in animal models of PD, and to determine whether Tenuigenin (TEN), a Chinese medicinal herb, can prevent α-synuclein-induced toxicity in a cell model. The levels of non-phosphorylated α-synuclein decreased over the course of PD, becoming increasingly phosphorylated and insoluble. There was a dramatic increase in phosphorylated α-synuclein that preceded LB formation. Importantly, three α-synuclein-related kinases [polo-like kinase 2 (PLK2), leucine-rich repeat kinase 2 (LRRK2) and cyclin G-associated kinase (GAK)] were found to be involved at different times in the evolution of LB formation in PD. Analysis of a subacute MPTP model of PD neurodegeneration revealed similar increases in S129P α-synuclein and PLK2/3 levels occurred immediately after the toxic insult, revealing this in vivo model as suitable to assess this molecular mechanism. Assessment of α-synuclein over-expressing cell models of PD cytotoxicity revealed increased S129P α-synuclein but no increase in PLK2/3 levels, however treatment of these cells with the Chinese herbal extract TEN was effective in reducing the increased S129P α-synuclein and cell toxicity in association with reducing levels of PLK3. This suggests that TEN may be an effective treatment for S129P α-synuclein induced cytotoxicity as observed in PD. In summary, these studies indicate that an increase in S129P α-synuclein occurs early in response to cell damage in both PD and toxin-induced PD models and that the levels of PLK2/3 increase in concert. Human data suggests that different kinases play a precipitating role in LB formation and compaction. Importantly TEN treatment appears to reduce PLK3 levels and ameliorate S129P α-synuclein toxicity, identifying this herbal extract as a potential therapeutic drug for this PD relevant mechanism."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["α-Synuclein phosphorylation and related kinases in Parkinson’s disease"]}]}],"canonical_facts":{"dc:creator":["Zhou, Jin-Xia"],"dc:date":["2013"],"dc:description":["Parkinson's disease (PD) is the most common neurodegenerative movement disorder pathologically identified by degeneration of the nigrostriatal system and the presence of Lewy bodies (LBs) and neurites, structural pathologies largely made from insoluble α-synuclein phosphorylated at serine 129 (S129P). Several kinases have been suggested to facilitate α-synuclein phosphorylation in PD, but without significant human data the changes that precipitate such pathology remain conjecture. The major aims of this project were to assess the dynamic changes of α-synuclein phosphorylation and related kinases in the progression of PD and in animal models of PD, and to determine whether Tenuigenin (TEN), a Chinese medicinal herb, can prevent α-synuclein-induced toxicity in a cell model. The levels of non-phosphorylated α-synuclein decreased over the course of PD, becoming increasingly phosphorylated and insoluble. There was a dramatic increase in phosphorylated α-synuclein that preceded LB formation. Importantly, three α-synuclein-related kinases [polo-like kinase 2 (PLK2), leucine-rich repeat kinase 2 (LRRK2) and cyclin G-associated kinase (GAK)] were found to be involved at different times in the evolution of LB formation in PD. Analysis of a subacute MPTP model of PD neurodegeneration revealed similar increases in S129P α-synuclein and PLK2/3 levels occurred immediately after the toxic insult, revealing this in vivo model as suitable to assess this molecular mechanism. Assessment of α-synuclein over-expressing cell models of PD cytotoxicity revealed increased S129P α-synuclein but no increase in PLK2/3 levels, however treatment of these cells with the Chinese herbal extract TEN was effective in reducing the increased S129P α-synuclein and cell toxicity in association with reducing levels of PLK3. This suggests that TEN may be an effective treatment for S129P α-synuclein induced cytotoxicity as observed in PD. In summary, these studies indicate that an increase in S129P α-synuclein occurs early in response to cell damage in both PD and toxin-induced PD models and that the levels of PLK2/3 increase in concert. Human data suggests that different kinases play a precipitating role in LB formation and compaction. Importantly TEN treatment appears to reduce PLK3 levels and ameliorate S129P α-synuclein toxicity, identifying this herbal extract as a potential therapeutic drug for this PD relevant mechanism."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/1959.4/53091","https://unsworks.unsw.edu.au/bitstreams/fa6bcc8e-6c2b-476f-a147-d2e0449541cf/download","https://doi.org/10.26190/unsworks/16526"],"dc:language":["EN"],"dc:publisher":["UNSW, Sydney"],"dc:rights":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"],"dc:subject":["Kinases","α-synuclein","Phosphorylation","Parkinson’s disease"],"dc:title":["α-Synuclein phosphorylation and related kinases in Parkinson’s disease"],"dc:type":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]},"updated_at":"2026-07-24T05:33:55Z"}