PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila.
Multisite hyperphosphorylation of tau has been implicated in the pathogenesis of neurodegenerative diseases including Alzheimer's disease (AD). However, the phosphorylation events critical for tau toxicity and mechanisms regulating these events are largely unknown. Here we show that Drosophila PAR-1 kinase initiates tau toxicity by triggering a temporally ordered phosphorylation process. PAR-1 directly phosphorylates tau at S262 and S356. This phosphorylation event is a prerequisite for the action of downstream kinases, including glycogen synthase kinase 3 (GSK-3) and cyclin-dependent kinase-5 (Cdk5), to phosphorylate several other sites and generate disease-associated phospho-epitopes. The initiator role of PAR-1 is further underscored by the fact that mutating PAR-1 phosphorylation sites causes a much greater reduction of overall tau phosphorylation and toxicity than mutating S202, one of the downstream sites whose phosphorylation depends on prior PAR-1 action. These findings begin to differentiate the effects of various phosphorylation events on tau toxicity and provide potential therapeutic targets.
Laboratory of Developmental Neurobiology, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Isao
I
Nishimura
Yufeng
Y
Yang
Bingwei
B
Lu
D000818:Animals; D030801:Animals, Genetically Modified; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism / Q000648:ultrastructure; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
D029721:Drosophila Proteins; D016875:tau Proteins; D011494:Protein Kinases; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; C495904:Cdk5 protein, Drosophila; D018844:Cyclin-Dependent Kinases; D038362:Glycogen Synthase Kinase 3; C472496:Par-1 protein, Drosophila