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PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is \u03b1\u2010synuclein (\u03b1\u2010syn). It was then found that \u03b1\u2010syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that \u03b1\u2010syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. \u03b1\u2010syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy\u2013lysosomal pathway (ALP). In this study, we initially explored how \u03b1\u2010syn phosphorylation by GRK6, PLK2 and CK2\u03b1 would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of \u03b1\u2010syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of \u03b1\u2010syn through ALP. To test this further in\u00a0vivo, we attenuate the proteasomal activity in a well\u2010established A53T \u03b1\u2010syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T \u03b1\u2010syn transgenic mice could reduce the accumulation of \u03b1\u2010syn in the striatum and midbrain. Based on our results, this study provides a new insight into how \u03b1\u2010syn is degraded through the UPS and ALP.<\/jats:p>","DOI":"10.1096\/fj.202401035r","type":"journal-article","created":{"date-parts":[[2024,10,22]],"date-time":"2024-10-22T09:20:33Z","timestamp":1729588833000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The role of polo\u2010like kinases 2 in the proteasomal and lysosomal degradation of alpha\u2010synuclein in neurons"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-0431","authenticated-orcid":false,"given":"Chun Chau","family":"Sung","sequence":"first","affiliation":[{"name":"Division of Life Science, State Key Laboratory of Molecular Neuroscience The Hong Kong University of Science and Technology  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6891-6128","authenticated-orcid":false,"given":"Wai Yun","family":"Lam","sequence":"additional","affiliation":[{"name":"Division of Life Science, State Key Laboratory of Molecular Neuroscience The Hong Kong University of Science and Technology  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4002-1338","authenticated-orcid":false,"given":"Kenny K. 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