Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2

Serine 129 (S129) phosphorylation of alpha-synuclein (alpha Syn) is a central feature of Lewy body (LB) disease pathology. 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 alpha Syn 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 alpha Syn (r-alpha Syn) 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-alpha Syn by CK2 in vitro. Introduction of Y136A r-alpha Syn oligomers into cultured cells exhibited increased levels of aggregates with S129 phosphorylation compared to wild-type r-alpha Syn oligomers. In addition, aggregate formation with S129 phosphorylation induced by introduction of wild-type r-alpha Syn 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 alpha Syn Y136 phosphorylation in the pathogenesis of LB disease and its potential as a therapeutic target.

Automated summary

The phosphorylation of alpha synuclein at Y136 in the Lewy body dementia brain is mediated by the unexpected kinase activity of CK2. CK2 can promote aggregate formation of r-alpha Syn with phosphorylation at S129 and Y136, while its inhibition attenuates the formation of aggregates with S129 phosphorylation and unexpectedly increases phosphorylation at Y136.