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

Abstract

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

• Authors: Kazunori Sano, Yasushi Iwasaki, Yuta Yamashita, Keiichi Irie, Masato Hosokawa, Katsuya Satoh, Kenichi Mishima
• Journal: Acta neuropathologica communications (Acta Neuropathol Commun) Vol. 9 Issue 1 Pg. 182 (11 12 2021) ISSN: 2051-5960 [Electronic] England
• PMID: 34772466 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• SNCA protein, human
• alpha-Synuclein
• Tyrosine
• Serine
• Casein Kinase II

Topics

• Aged
• Aged, 80 and over
• Amino Acid Substitution
• Autopsy
• Brain (pathology)
• Casein Kinase II (metabolism)
• Cells, Cultured
• Female
• Humans
• Lewy Body Disease (metabolism, pathology)
• Male
• Mutation
• Phosphorylation
• Serine (metabolism)
• Tyrosine (metabolism)
• alpha-Synuclein (metabolism)