title: Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated.
abstract: Abnormal phosphorylation of the microtubule-associated protein tau is observed in many neurodegenerative diseases, including Alzheimer's disease (AD). AD-related phosphorylation of two tau residues, Ser262 and Ser356, by PAR-1/MARK stabilizes tau in the initial phase of mismetabolism, leading to subsequent phosphorylation events, accumulation, and toxicity. However, the relative contribution of phosphorylation at each of these sites to tau stabilization has not yet been elucidated. In a Drosophila model of human tau toxicity, we found that tau was phosphorylated at Ser262, but not at Ser356, and that blocking Ser262 phosphorylation decreased total tau levels. By contrast, when PAR-1 was co-overexpressed with tau, tau was hyperphosphorylated at both Ser262 and Ser356. Under these conditions, the protein levels of tau were significantly elevated, and prevention of tau phosphorylation at both residues was necessary to completely suppress this elevation. These results suggest that tau phosphorylation at Ser262 plays the predominant role in tau stabilization when PAR-1/MARK activity is normal, whereas Ser356 phosphorylation begins to contribute to this process when PAR-1/MARK activity is abnormally elevated, as in diseased brains.
authors: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan. Electronic address: k_ando@tmu.ac.jp.
authors: Kanae
authors: K
authors: Ando
authors: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
authors: Mikiko
authors: M
authors: Oka
authors: Department of Neuroscience, Thomas Jefferson University, Philadelphia, PA, USA.
authors: Yosuke
authors: Y
authors: Ohtake
authors: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
authors: Motoki
authors: M
authors: Hayashishita
authors: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
authors: Sawako
authors: S
authors: Shimizu
authors: Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Japan.
authors: Shin-Ichi
authors: S
authors: Hisanaga
authors: Department of Alzheimer's Disease Research, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan. Electronic address: iijimakm@ncgg.go.jp.
authors: Koichi M
authors: KM
authors: Iijima
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D006801:Humans; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D055550:Protein Stability; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D016875:tau Proteins; D010768:Phosphoserine; D038362:Glycogen Synthase Kinase 3; C472496:Par-1 protein, Drosophila
keywords: Alzheimer's disease; Drosophila; Neurodegeneration; PAR-1/MARK; Phosphorylation; Tau