2021 Fiscal Year Final Research Report
Identification of pathogenic alpha-synuclein species that exhibit prion-like properties in Lewy body dementia, and basic research for drug development
| Project/Area Number |
19K07858
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (C)
|
| Allocation Type | Multi-year Fund |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 51030:Pathophysiologic neuroscience-related
|
|---|
| Research Institution | Fukuoka University |
|---|
Principal Investigator |
|
|---|
| Project Period (FY) |
2019-04-01 – 2022-03-31
|
| Keywords | レビー小体型認知症 / α-シヌクレイン / プリオン様伝播 / S129リン酸化 / Y136リン酸化 / Casein kinaseⅡ |
|---|
| Outline of Final Research Achievements |
We found that α-synuclein (αSyn) aggregates are predominantly phosphorylated at Y136 in the Lewy body dementia (LBD) brain. Aggregate formation with S129 and Y136 phosphorylation of recombinant αSyn (r-αSyn) were induced by Casein kinase 2 (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 LBD and its potential as a therapeutic target.
|
| Free Research Field |
神経内科学
|
| Academic Significance and Societal Importance of the Research Achievements |
2002年にレビー小体型認知症（LBD）脳における異常αSynのS129リン酸化が同定されたものの、そのリン酸化機序や役割は不明確なままである。このことはS129リン酸化に影響する因子の存在を示唆しており、本研究ではその因子としてY136リン酸化を世界で初めて同定した。
S129リン酸化が見られる疾患にはパーキンソン病（PD）もあり、LBDやPDに対する現在の治療法は対症療法のみである。根治療法が確立されない要因として、異常αSyn本体が未解明なことが挙げられ、本研究成果で見出した異常αSynのY136リン酸化やオリゴマー構造は、LBD、PDの病態解明、根治療法開発への基盤になりうると考える。
|
