Tau phosphorylation sites work in concert to promote neurotoxicity in vivo.
Tau is a microtubule binding protein implicated in a number of human neurodegenerative disorders, including Alzheimer's disease. Phosphorylation of serine-proline/threonine-proline sites, targeted by proline-directed kinases, coincides temporally with neurodegeneration in the human diseases. Recently, we demonstrated that this unique group of serines and threonines has a critical role in controlling tau toxicity in a Drosophila model of tauopathy. Here, we use a combination of genetic and biochemical approaches to examine these sites individually and to determine which of them is primarily responsible for controlling tau neurotoxicity. Despite the importance placed on individual phosphoepitopes and their contributions to disease pathogenesis, our results indicate that no single phosphorylation residue plays a dominant role in controlling tau toxicity. These findings suggest that serine-proline/threonine-proline sites cooperate to mediate neurodegeneration in vivo.
Steinhilb
Michelle L
ML
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Dias-Santagata
Dora
D
Fulga
Tudor A
TA
Felch
Daniel L
DL
Feany
Mel B
MB
D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D002453:Cell Cycle; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011494:Protein Kinases; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D000596:Amino Acids; D029721:Drosophila Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases; D016875:tau Proteins; C416303:target of rapamycin protein, Drosophila