Journal
JOURNAL OF NEUROSCIENCE RESEARCH
Volume 85, Issue 6, Pages 1271-1278Publisher
WILEY-LISS
DOI: 10.1002/jnr.21232
Keywords
Alzheimer's disease; kinase; neurodegeneration; phosphorylation; tauopathy
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Funding
- NIA NIH HHS [AG05134, AG19790] Funding Source: Medline
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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. (C) 2007 Wiley-Liss, Inc.
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