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

We have shown in the parkinsonism-inducing neurotoxin MPP+/MPTP model that alpha-Synuclein (alpha-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 3 beta (GSK-3 beta), is robustly activated in various MPP+/MPTP models of Parkinsonism (SH-SY5Y cotransfected cells, mesencephalic neurons, transgenic mice overexpressing alpha-Syn, and postmortem striatum of PD patients). The activation of GSK-3 beta was absolutely dependent on the presence of alpha-Syn, as indexed by the absence of p-GSK-3 beta in cells lacking alpha-Syn and in alpha-Syn KO mice. MPP+ treatment induced translocation and accumulation of p-GSK-3 beta in nuclei of SH-SY5Y cells and mesencephalic neurons. Through coimmunoprecipitation (co-IP), we found that alpha-Syn, pSer396/404-Tau, and p-GSK-3 beta exist as a heterotrimeric complex in SH-SY5Y cells. GSK-3 beta inhibitors (lithium and TDZD-8) protected against MPP+-induced events in SH-SY5Y cells, preventing cell death and p-GSK-3 beta formation, by reversing increases in alpha-Syn accumulation and p-Tau formation. These data unveil a previously unappreciated role of alpha-Syn in the induction of p-GSK-3 beta, 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. alpha-Synuclein contributes to GSK-3 beta-catalyzed Tau phosphorylation in Parkinson's disease models. FASEB J. 23, 2820-2830 (2009). www.fasebj.org