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 t...

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Autores principales:	Kazunori Sano, Yasushi Iwasaki, Yuta Yamashita, Keiichi Irie, Masato Hosokawa, Katsuya Satoh, Kenichi Mishima
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	α-Synuclein Lewy body dementia Y136 phosphorylation S129 phosphorylation Casein kinase 2 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/8339408d5c114b4fb7b233af1180672c
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spelling	oai:doaj.org-article:8339408d5c114b4fb7b233af1180672c2021-11-14T12:11:13ZTyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 210.1186/s40478-021-01281-92051-5960https://doaj.org/article/8339408d5c114b4fb7b233af1180672c2021-11-01T00:00:00Zhttps://doi.org/10.1186/s40478-021-01281-9https://doaj.org/toc/2051-5960Abstract 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.Kazunori SanoYasushi IwasakiYuta YamashitaKeiichi IrieMasato HosokawaKatsuya SatohKenichi MishimaBMCarticleα-SynucleinLewy body dementiaY136 phosphorylationS129 phosphorylationCasein kinase 2Neurology. Diseases of the nervous systemRC346-429ENActa Neuropathologica Communications, Vol 9, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	α-Synuclein Lewy body dementia Y136 phosphorylation S129 phosphorylation Casein kinase 2 Neurology. Diseases of the nervous system RC346-429
spellingShingle	α-Synuclein Lewy body dementia Y136 phosphorylation S129 phosphorylation Casein kinase 2 Neurology. Diseases of the nervous system RC346-429 Kazunori Sano Yasushi Iwasaki Yuta Yamashita Keiichi Irie Masato Hosokawa Katsuya Satoh Kenichi Mishima Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
description	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.
format	article
author	Kazunori Sano Yasushi Iwasaki Yuta Yamashita Keiichi Irie Masato Hosokawa Katsuya Satoh Kenichi Mishima
author_facet	Kazunori Sano Yasushi Iwasaki Yuta Yamashita Keiichi Irie Masato Hosokawa Katsuya Satoh Kenichi Mishima
author_sort	Kazunori Sano
title	Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
title_short	Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
title_full	Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
title_fullStr	Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
title_full_unstemmed	Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
title_sort	tyrosine 136 phosphorylation of α-synuclein aggregates in the lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2
publisher	BMC
publishDate	2021
url	https://doaj.org/article/8339408d5c114b4fb7b233af1180672c
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Tyrosine 136 phosphorylation of α-synuclein aggregates in the Lewy body dementia brain: involvement of serine 129 phosphorylation by casein kinase 2

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