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

✍ Scribed by Michelle L. Steinhilb; Dora Dias-Santagata; Erin E. Mulkearns; Joshua M. Shulman; Jacek Biernat; Eva-Maria Mandelkow; Mel B. Feany

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: English
• Weight: 368 KB
• Volume: 85
• Category: Article
• ISSN: 0360-4012
• DOI: 10.1002/jnr.21232

✦ Synopsis

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. © 2007 Wiley‐Liss, Inc.