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Although the neighboring tyrosine residues Y125, Y133, and Y136 are also phosphorylation sites, little is known regarding potential roles of phosphorylation cross-talk between these sites and its involvement in the pathogenesis of LB disease. Here, we found that \u03b1Syn aggregates are predominantly phosphorylated at Y136 in the Lewy body dementia brain, which is mediated by unexpected kinase activity of Casein kinase 2 (CK2). Aggregate formation with S129 and Y136 phosphorylation of recombinant \u03b1Syn (r-\u03b1Syn) were induced by CK2 but abolished by replacement of S129 with alanine (S129A) in vitro. Mutation of Y136 to alanine (Y136A) promoted aggregate formation and S129 phosphorylation of r-\u03b1Syn by CK2 in vitro. Introduction of Y136A r-\u03b1Syn oligomers into cultured cells exhibited increased levels of aggregates with S129 phosphorylation compared to wild-type r-\u03b1Syn oligomers. In addition, aggregate formation with S129 phosphorylation induced by introduction of wild-type r-\u03b1Syn oligomers was significantly attenuated by CK2 inhibition, which resulted in an unexpected increase in Y136 phosphorylation in cultured cells. Our findings suggest the involvement of CK2-related \u03b1Syn Y136 phosphorylation in the pathogenesis of LB disease and its potential as a therapeutic target.<\/jats:p>","DOI":"10.1186\/s40478-021-01281-9","type":"journal-article","created":{"date-parts":[[2021,11,12]],"date-time":"2021-11-12T13:02:52Z","timestamp":1636722172000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Tyrosine 136 phosphorylation of \u03b1-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2"],"prefix":"10.1186","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5198-5642","authenticated-orcid":false,"given":"Kazunori","family":"Sano","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Iwasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiichi","family":"Irie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Hosokawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuya","family":"Satoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenichi","family":"Mishima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,12]]},"reference":[{"key":"1281_CR1","doi-asserted-by":"publisher","first-page":"29739","DOI":"10.1074\/jbc.M600933200","volume":"281","author":"JP Anderson","year":"2006","unstructured":"Anderson JP, Walker DE, Goldstein JM, de Laat R, Banducci K, Caccavello RJ, Barbour R, Huang J, Kling K, Lee M et al (2006) Phosphorylation of Ser-129 is the dominant pathological modification of alpha-synuclein in familial and sporadic Lewy body disease. 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Informed consent was obtained from the patients and\/or their families.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Consent for the use of the brain tissue for research purposes and for publication was obtained from the patients and\/or their families.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors report no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"182"}}