We have shown in the parkinsonism-inducing neurotoxin MPP + /MPTP model that α-Synuclein (α-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 α-Syn, and postmortem striatum of PD patients). The activation of GSK-3β was absolutely dependent on the presence of α-Syn, as indexed by the absence of p-GSK-3β in cells lacking α-Syn and in α-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 α-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 α-Syn accumulation and p-Tau formation. These data unveil a previously unappreciated role of α-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. α-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models.
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α-Synuclein contributes to GSK-3β-catalyzed Tau phosphorylation in Parkinson’s disease models
Duka, Tetyana; Duka, Valeriy; Joyce, Jeffrey N.; Sidhu, Anita
Follow The FASEB Journal
, Volume 23 (9): 2820
Fed of American Socs for Experimental Biology – Sep 1, 2009
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