Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Animals, Genetically Modified
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Apoptosis / genetics
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Armadillo Domain Proteins
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Disease Models, Animal
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Drosophila Proteins*
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Drosophila melanogaster / growth & development*
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Drosophila melanogaster / metabolism
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Drosophila melanogaster / ultrastructure
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Eye Abnormalities / genetics*
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Eye Abnormalities / metabolism
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Eye Abnormalities / pathology
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Glycogen Synthase Kinase 3
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Glycogen Synthase Kinases
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High Mobility Group Proteins / genetics
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High Mobility Group Proteins / metabolism
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Humans
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Inhibitor of Apoptosis Proteins
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Insect Proteins / genetics*
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Insect Proteins / metabolism
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Insect Proteins / ultrastructure
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Mutation / genetics
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Nervous System Malformations / genetics*
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Nervous System Malformations / metabolism
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Nervous System Malformations / pathology
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Neurofibrillary Tangles / genetics*
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Neurofibrillary Tangles / pathology
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Neurofibrillary Tangles / ultrastructure
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Phenotype
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Photoreceptor Cells, Invertebrate / abnormalities*
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Photoreceptor Cells, Invertebrate / pathology
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Photoreceptor Cells, Invertebrate / ultrastructure
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Trans-Activators*
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Transcription Factors*
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Transgenes / genetics
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beta Catenin
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tau Proteins / genetics*
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tau Proteins / metabolism
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tau Proteins / ultrastructure
Substances
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ARM protein, Drosophila
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Armadillo Domain Proteins
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CTNNB1 protein, human
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Cytoskeletal Proteins
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DIAP1 protein, Drosophila
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DIAP2 protein, Drosophila
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Drosophila Proteins
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High Mobility Group Proteins
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Inhibitor of Apoptosis Proteins
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Insect Proteins
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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beta Catenin
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pan protein, Drosophila
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tau Proteins
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wingless protein, Sarcophaga
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Glycogen Synthase Kinases
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Protein Serine-Threonine Kinases
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Sgg protein, Drosophila
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3