S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila

J Neurosci Res. 2007 May 1;85(6):1271-8. doi: 10.1002/jnr.21232.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine / genetics
  • Animals
  • Animals, Genetically Modified
  • Disease Models, Animal
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Enzyme Activation / physiology
  • Eye / pathology
  • Eye / ultrastructure
  • Microscopy, Electron, Scanning / methods
  • Mutation / physiology
  • Neurotoxicity Syndromes / enzymology*
  • Neurotoxicity Syndromes / genetics
  • Neurotoxicity Syndromes / pathology
  • Phosphoric Monoester Hydrolases / metabolism
  • Phosphorylation
  • Proline-Directed Protein Kinases / metabolism*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • tau Proteins / physiology*

Substances

  • Drosophila Proteins
  • tau Proteins
  • Protein Kinases
  • Proline-Directed Protein Kinases
  • Phosphoric Monoester Hydrolases
  • Alanine