Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila.
Pathologic alterations in the microtubule-associated protein tau have been implicated in a number of neurodegenerative disorders, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and frontotemporal dementia (FTD). Here, we show that tau overexpression, in combination with phosphorylation by the Drosophila glycogen synthase kinase-3 (GSK-3) homolog and wingless pathway component (Shaggy), exacerbated neurodegeneration induced by tau overexpression alone, leading to neurofibrillary pathology in the fly. Furthermore, manipulation of other wingless signaling molecules downstream from shaggy demonstrated that components of the Wnt signaling pathway modulate neurodegeneration induced by tau pathology in vivo but suggested that tau phosphorylation by GSK-3beta differs from canonical Wnt effects on beta-catenin stability and TCF activity. The genetic system we have established provides a powerful reagent for identification of novel modifiers of tau-induced neurodegeneration that may serve as future therapeutic targets.
Jackson
George R
GR
Neurogenetics Program, Department of Neurology, University of California-Los Angeles, School of Medicine, 710 Westwood Plaza, 90095, USA. grjackson@mednet.ucla.edu
Wiedau-Pazos
Martina
M
Sang
Tzu-Kang
TK
Wagle
Naveed
N
Brown
Carlos A
CA
Massachi
Sasan
S
Geschwind
Daniel H
DH
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis / Q000235:genetics; D051186:Armadillo Domain Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D004331:Drosophila melanogaster / Q000254:growth & development* / Q000378:metabolism / Q000648:ultrastructure; D005124:Eye Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation / Q000235:genetics; D009421:Nervous System Malformations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000002:abnormalities* / Q000473:pathology / Q000648:ultrastructure; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics; D051176:beta Catenin; D016875:tau Proteins / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure
C495305:ARM protein, Drosophila; D051186:Armadillo Domain Proteins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; C111891:DIAP1 protein, Drosophila; C111892:DIAP2 protein, Drosophila; D029721:Drosophila Proteins; D006609:High Mobility Group Proteins; D051034:Inhibitor of Apoptosis Proteins; D019476:Insect Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin; C115159:pan protein, Drosophila; D016875:tau Proteins; C105170:wingless protein, Sarcophaga; D038341:Glycogen Synthase Kinases; D017346:Protein Serine-Threonine Kinases; C080335:Sgg protein, Drosophila; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3