Glycogen synthase kinase 3 β activity is essential for Polo-like kinase 2-and Leucine-rich repeat kinase 2-mediated regulation of α-synuclein

NEUROBIOLOGY OF DISEASE

卷:136

Article

Kofoed, Rikke H.^1,2  Betzer, Cristine¹  Ferreira, Nelson¹  Jensen, Poul Henning¹ 

[1] Aarhus Univ, DANDRITE Danish Res Inst Translat Neurosci, Dept Biomed, Ole Worms Alle 8, DK-8000 Aarhus, Denmark

[2] Sunnybrook Res Inst, Biol Sci, 2075 Bayview Ave, Toronto, ON M4N 3M5, Canada

关键词: Parkinson's disease;    alpha-Synuclein;    Polo-like kinase 2;    Glycogen synthase kinase 3 beta;    Leucine-rich repeat kinase 2;   

DOI  :  10.1016/j.nbd.2019.104720

来源: Elsevier

【 摘 要 】

Parkinson's disease (PD) is a currently incurable disease and the number of patients is expected to increase due to the extended human lifespan. alpha-Synuclein is a pathological hallmark of PD and variations and triplication of the gene encoding alpha-synuclein are strongly correlated with the risk of developing PD. Decreasing alpha-synuclein is therefore a promising therapeutic strategy for the treatment of PD. We have previously demonstrated that Polo-like kinase 2 (PLK-2) regulates alpha-synuclein protein levels by modulating the expression of alpha-synuclein mRNA. In this study, we further expand the knowledge on this pathway and show that it depends on down-stream modulation of Glycogen-synthase kinase 3 beta (GSK-3 beta). We show that PLK-2 inhibition only increases alpha-synuclein levels in the presence of active GSK-3 beta in both cell lines and primary neuronal cultures. Furthermore, direct inhibition of GSK-3 beta decreases alpha-synuclein protein and mRNA levels in our cell model and overexpression of Leucine-rich repeat kinase 2, known to activate GSK-3 beta, increases alpha-synuclein levels. Finally, we show an increase in endogenous alpha-synuclein in primary neurons when increasing GSK-3 beta activity. Our findings demonstrate a not previously described role of endogenous GSK-3 beta activity in the PLK-2 mediated regulation of alpha-synuclein levels. This finding opens up the possibility of GSK-3 beta as a novel target for decreasing alpha-synuclein levels by the use of small molecule compounds, hereby serving as a disease modulating strategy.