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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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.

Original languageEnglish
Article number104720
JournalNeurobiology of Disease
Volume136
ISSN0969-9961
DOIs
Publication statusPublished - Mar 2020

    Research areas

  • Glycogen synthase kinase 3β, Leucine-rich repeat kinase 2, Parkinson's disease, Polo-like kinase 2, α-Synuclein

See relations at Aarhus University Citationformats

ID: 175408451