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Protein clearance appears as a regulator of the \u2018<jats:italic>\u03b1<\/jats:italic>\u2010Syn burden\u2019 underlying PD pathogenesis. The picture emerging is that a combination of pathways with complementary roles, including the Proteasome System and the Autophagy\u2013Lysosome Pathway, contributes to the intracellular degradation of <jats:italic>\u03b1<\/jats:italic>\u2010Syn. This study addresses the mechanisms governing the degradation of <jats:italic>\u03b1<\/jats:italic>\u2010Syn species seeded by exogenous fibrils in neuronally differentiated SH\u2010SY5Y neuroblastoma cells with inducible expression of <jats:italic>\u03b1<\/jats:italic>\u2010Syn. Using human <jats:italic>\u03b1<\/jats:italic>\u2010Syn recombinant fibrils (pre\u2010formed fibrils, PFFs), seeding and aggregation of endogenous Proteinase K (PK)\u2010resistant <jats:italic>\u03b1<\/jats:italic>\u2010Syn species occurs within a time frame of 6\u00a0days, and is still prominent after 12\u00a0days of PFF addition. Clearance of <jats:italic>\u03b1<\/jats:italic>\u2010Syn assemblies in this inducible model was enhanced after switching off <jats:italic>\u03b1<\/jats:italic>\u2010Syn expression with doxycycline. Lysosomal inhibition led to accumulation of SDS\u2010soluble <jats:italic>\u03b1<\/jats:italic>\u2010Syn aggregates 6\u00a0days after PFF\u2010addition or when switching off <jats:italic>\u03b1<\/jats:italic>\u2010Syn expression. Additionally, the autophagic enhancer, rapamycin, induced the clearance of <jats:italic>\u03b1<\/jats:italic>\u2010Syn aggregates 13\u00a0days post\u2010PFF addition, indicating that autophagy is the major pathway for aggregated <jats:italic>\u03b1<\/jats:italic>\u2010Syn clearance. SDS\u2010soluble phosphorylated <jats:italic>\u03b1<\/jats:italic>\u2010Syn at S129 was only apparent at 7\u00a0days of incubation with a higher amount of PFFs.\u00a0Proteasomal inhibition resulted in further accumulation of SDS\u2010soluble phosphorylated <jats:italic>\u03b1<\/jats:italic>\u2010Syn at S129, with limited PK resistance. Our data suggest that in this inducible model autophagy is mainly responsible for the degradation of fibrillar <jats:italic>\u03b1<\/jats:italic>\u2010Syn, whereas the proteasome system is responsible, at least in part, for the selective clearance of phosphorylated <jats:italic>\u03b1<\/jats:italic>\u2010Syn oligomers.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15174-fig-0008-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.15174","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T04:54:49Z","timestamp":1598936089000},"page":"880-896","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Distinct alpha\u2010Synuclein species induced by seeding are selectively cleared by the Lysosome or the Proteasome in neuronally differentiated SH\u2010SY5Y cells"],"prefix":"10.1111","volume":"156","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8262-6274","authenticated-orcid":false,"given":"Marina","family":"Pantazopoulou","sequence":"first","affiliation":[{"name":"Biomedical Research Foundation of the Academy of Athens Athens 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and Laboratory of Neurodegenerative Diseases Institut Francois Jacob (MIRCen) CNRS Fontenay\u2010Aux\u2010Roses cedex France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3569-8990","authenticated-orcid":false,"given":"Leonidas","family":"Stefanis","sequence":"additional","affiliation":[{"name":"Biomedical Research Foundation of the Academy of Athens Athens 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