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Glycogen Synthase Kinase 3 β Activity Is Essential for Polo-like Kinase 2- And Leucine-rich Repeat Kinase 2-mediated Regulation of α-synuclein

Glycogen Synthase Kinase 3 β Activity Is Essential for Polo-like Kinase 2- And Leucine-rich Repeat Kinase 2-mediated Regulation of α-synuclein

Rikke H Kofoed, Cristine Betzer, Nelson Ferreira, Poul Henning Jensen

Neurobiol Dis. 2020 Mar;136:104720.

PMID: 31881263

Abstract:

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

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42414862	PLK2 Active human			Price

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