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Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models.
FASEB J. 2009 Sep; 23(9):2820-30.FJ

Abstract

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.

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Authors+Show Affiliations

Duka T
Department of Biochemistry, Molecular and Cellular Biology, Georgetown University, Washington, District of Columbia, USA.
Duka V
No affiliation info available
Joyce JN
No affiliation info available
Sidhu A
No affiliation info available

MeSH

AnimalsCatalysisDisease Models, AnimalGlycogen Synthase Kinase 3Glycogen Synthase Kinase 3 betaHumansMiceMice, TransgenicNeurodegenerative DiseasesParkinson DiseasePhosphorylationTranscriptional Activationalpha-Synucleintau Proteins

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19369384

Citation

Duka, Tetyana, et al. "Alpha-Synuclein Contributes to GSK-3beta-catalyzed Tau Phosphorylation in Parkinson's Disease Models." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 23, no. 9, 2009, pp. 2820-30.
Duka T, Duka V, Joyce JN, et al. Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models. FASEB J. 2009;23(9):2820-30.
Duka, T., Duka, V., Joyce, J. N., & Sidhu, A. (2009). Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 23(9), 2820-30. https://doi.org/10.1096/fj.08-120410
Duka T, et al. Alpha-Synuclein Contributes to GSK-3beta-catalyzed Tau Phosphorylation in Parkinson's Disease Models. FASEB J. 2009;23(9):2820-30. PubMed PMID: 19369384.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alpha-Synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson's disease models. AU - Duka,Tetyana, AU - Duka,Valeriy, AU - Joyce,Jeffrey N, AU - Sidhu,Anita, Y1 - 2009/04/15/ PY - 2009/4/17/entrez PY - 2009/4/17/pubmed PY - 2009/10/24/medline SP - 2820 EP - 30 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J VL - 23 IS - 9 N2 - 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/19369384/Alpha_Synuclein_contributes_to_GSK_3beta_catalyzed_Tau_phosphorylation_in_Parkinson's_disease_models_ L2 - https://doi.org/10.1096/fj.08-120410 DB - PRIME DP - Unbound Medicine ER -