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-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models

Tetyana Duka^*, Valeriy Duka^*, Jeffrey N. Joyce and Anita Sidhu^*,1

^* Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia, USA; and

Department of Research, Maricopa Integrated Health System, Phoenix, Arizona, USA

¹ Correspondence: Laboratory of Molecular Neurochemistry, The Research Bldg., Rm. W222, 3970 Reservoir Rd., NW, Washington, D.C. 20007, USA. E-mail: sidhua{at}georgetown.edu

We have shown in the parkinsonism-inducing neurotoxin MPP⁺/MPTP model that -Synuclein (-Syn), a presynaptic protein causal in Parkinson’s disease (PD), contributes to hyperphosphorylation of Tau (p-Tau), a protein normally linked to tauopathies, such as Alzheimer’s disease (AD). Here, we investigated the kinase involved and show that the Tau-specific kinase, glycogen synthase kinase 3β (GSK-3β), is robustly activated in various MPP⁺/MPTP models of Parkinsonism (SH-SY5Y cotransfected cells, mesencephalic neurons, transgenic mice overexpressing -Syn, and postmortem striatum of PD patients). The activation of GSK-3β was absolutely dependent on the presence of -Syn, as indexed by the absence of p-GSK-3β in cells lacking -Syn and in -Syn KO mice. MPP⁺ treatment induced translocation and accumulation of p-GSK-3β in nuclei of SH-SY5Y cells and mesencephalic neurons. Through coimmunoprecipitation (co-IP), we found that -Syn, pSer396/404-Tau, and p-GSK-3β exist as a heterotrimeric complex in SH-SY5Y cells. GSK-3β inhibitors (lithium and TDZD-8) protected against MPP⁺-induced events in SH-SY5Y cells, preventing cell death and p-GSK-3β formation, by reversing increases in -Syn accumulation and p-Tau formation. These data unveil a previously unappreciated role of -Syn in the induction of p-GSK-3β, and demonstrate the importance of this kinase in the genesis and maintenance of neurodegenerative changes associated with PD.—Duka, T., Duka, V., Joyce, J. N., Sidhu, A. -Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models.

Key Words: synucleopathies • tauopathies • neurodegeneration • Alzheimer’s disease