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

• Published in: Neurobiology of disease Vol. 136; p. 104720
• Main Authors: Kofoed, Rikke H., Betzer, Cristine, Ferreira, Nelson, Jensen, Poul Henning
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2020; Elsevier
• Subjects: alpha-Synuclein - genetics; alpha-Synuclein - metabolism; Animals; Glycogen Synthase Kinase 3 beta - genetics; Glycogen Synthase Kinase 3 beta - metabolism; Glycogen synthase kinase 3β; HEK293 Cells; Humans; Leucine-rich repeat kinase 2; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; Mice; Mice, Inbred C57BL; Parkinson's disease; Polo-like kinase 2; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; α-Synuclein; PLK-2i; α-Synuclein; GSK-3i XV; Parkinson's disease; Leucine-rich repeat kinase 2; GWAS; Polo-like kinase 2; pS129; Glycogen synthase kinase 3β; LRRK2; pS935; WB; GSK-3β; SD; PD; FCS; pS9; SNPs; MPTP; pS396; PLK-2
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.104720

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. •Inhibition of Polo-like kinase 2 increases α-synuclein mRNA levels in a Glycogen synthase kinase 3β-dependent manner.•Glycogen synthase kinase 3β inhibition decreases α-synuclein and abolishes the effect of Polo-like kinase 2 inhibition.•Leucine-rich repeat kinase 2 overexpression increases α-synuclein in a Glycogen synthase kinase 3β-dependent manner.•Increased GSK-3β activity increases Tau phosphorylation and endogenous α-synuclein levels in primary mouse neurons.