S/P and T/P phosphorylation is critical for tau neurotoxicity in Drosophila.
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.
Steinhilb
Michelle L
ML
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Dias-Santagata
Dora
D
Mulkearns
Erin E
EE
Shulman
Joshua M
JM
Biernat
Jacek
J
Mandelkow
Eva-Maria
EM
Feany
Mel B
MB
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*
D029721:Drosophila Proteins; D016875:tau Proteins; D011494:Protein Kinases; D038461:Proline-Directed Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D000409:Alanine