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

We have shown in the parknsonism‐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 SHSY5Y 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 SHSY5Y 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. FASEB J. 23, 2820–2830 (2009). www.fasebj.org