The FASEB Journal · 2009 · 261 citations · 51 references
Molecular BiologySocial SciencesAutophagyAlpha-syn Ko MiceDegenerative PathologyProtein MisfoldingCell SignalingDisease ModelsMolecular NeuroscienceBiochemistryAlpha-syn AccumulationNeuroprotectionCell BiologyPd PatientsNeurodegenerative DiseasesSignal TransductionNeuroscienceMolecular NeurobiologySystems BiologyMedicine
Alpha‑Synuclein contributes to hyperphosphorylation of Tau in the MPP(+)/MPTP Parkinsonism model, linking a presynaptic PD protein to a hallmark of tauopathies. The study aimed to identify the kinase responsible for this effect. GSK‑3β was found to be robustly activated across multiple MPP(+)/MPTP models, including SH‑SY5Y cells, mesencephalic neurons, transgenic alpha‑Syn mice, and postmortem PD striatum. Activation of GSK‑3β requires alpha‑Syn, as it is absent in alpha‑Syn‑deficient cells and mice; MPP(+) induces nuclear p‑GSK‑3β, which complexes with alpha‑Syn and p‑Ser396/404‑Tau, and GSK‑3β inhibitors prevent MPP(+)‑induced cell death and p‑Tau formation, highlighting alpha‑Syn’s role in driving GSK‑3β‑mediated neurodegeneration.
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 3beta (GSK-3beta), 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-3beta was absolutely dependent on the presence of alpha-Syn, as indexed by the absence of p-GSK-3beta in cells lacking alpha-Syn and in alpha-Syn KO mice. MPP(+) treatment induced translocation and accumulation of p-GSK-3beta in nuclei of SH-SY5Y cells and mesencephalic neurons. Through coimmunoprecipitation (co-IP), we found that alpha-Syn, pSer396/404-Tau, and p-GSK-3beta exist as a heterotrimeric complex in SH-SY5Y cells. GSK-3beta inhibitors (lithium and TDZD-8) protected against MPP(+)-induced events in SH-SY5Y cells, preventing cell death and p-GSK-3beta 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-3beta, and demonstrate the importance of this kinase in the genesis and maintenance of neurodegenerative changes associated with PD.
51
α-Synuclein Locus Triplication Causes Parkinson's Disease
Andrew Singleton · Science · 2003 · 4.3K citations
Mitophagy, Farnesyltransferase Inhibition, Social Sciences +16