title: S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila.
abstract: The microtubule-associated protein tau is hyperphosphorylated abnormally in AD and related neurodegenerative disorders. Many phospho epitopes created by proline directed kinases (SP/TP sites) show relative specificity for disease states. To test whether phosphorylation at the disease-associated SP/TP sites affects tau toxicity in vivo, we expressed a form of tau in Drosophila in which all SP/TP sites are mutated to alanine. We find that blocking phosphorylation at SP/TP motifs markedly reduces tau toxicity in vivo. Using phosphorylation-specific antibodies, we identify a positive correlation between increased phosphorylation at disease-associated sites and neurotoxicity. We use the phosphorylation-incompetent version of tau to show that kinase and phosphatase modifiers of tau neurotoxicity, including cdk5/p35, the JNK kinase hemipterous and PP2A act via SP/TP phosphorylation sites. We provide direct evidence in an animal model system to support the role of phosphorylation at SP/TP sites in playing a critical role in tau neurotoxicity.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Steinhilb
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulkearns
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
authors.forename: Mel B
authors.initials: MB
authors.lastname: Feany
mesh_terms: D000409:Alanine / Q000235:genetics; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D005123:Eye / Q000473:pathology / Q000648:ultrastructure; D008855:Microscopy, Electron, Scanning / Q000379:methods; D009154:Mutation / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D038461:Proline-Directed Protein Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000502:physiology*
chemical_list: D029721:Drosophila Proteins; D016875:tau Proteins; D011494:Protein Kinases; D038461:Proline-Directed Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D000409:Alanine