Abstract
Neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated and ubiquitylated tau, are exhibited at regions where neuronal loss occurs in neurodegenerative diseases; however, the mechanisms of NFT formation remain unknown. Molecular studies of frontotemporal dementia with parkinsonism-17 demonstrated that increasing the ratio of tau with exon 10 insertion induced fibrillar tau accumulation. Here, we show that carboxyl terminus of Hsc70-interacting protein (CHIP), a U-box protein, recognizes the microtubule-binding repeat region of tau and preferentially ubiquitylates four-repeat tau compared with three-repeat tau. Overexpression of CHIP induced the prompt degradation of tau, reduced the formation of detergent-insoluble tau and inhibited proteasome inhibitor-induced cell death. NFT bearing neurons in progressive supranuclear palsy, in which four-repeat tau is a component, showed the accumulation of CHIP. Thus, CHIP is a ubiquitin ligase for four-repeat tau and maintains neuronal survival by regulating the quality control of tau in neurons.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Death / drug effects
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Cell Death / genetics
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Cell Line
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Cell Survival / drug effects
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Cell Survival / genetics
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Chlorocebus aethiops
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Cysteine Endopeptidases / metabolism
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Enzyme Inhibitors / pharmacology
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HSC70 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / metabolism*
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Humans
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Mice
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Multienzyme Complexes / antagonists & inhibitors
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Multienzyme Complexes / metabolism
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Mutagenesis, Site-Directed
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Neurons / drug effects
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Neurons / metabolism
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Proteasome Endopeptidase Complex
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Protein Binding / genetics
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Protein Binding / physiology
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RNA Interference
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repetitive Sequences, Amino Acid / genetics
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Repetitive Sequences, Amino Acid / physiology*
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Sequence Deletion
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Tauopathies / metabolism*
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Tauopathies / pathology
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Transfection
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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tau Proteins / genetics
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tau Proteins / metabolism*
Substances
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Enzyme Inhibitors
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HSC70 Heat-Shock Proteins
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HSP70 Heat-Shock Proteins
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HSPA8 protein, human
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Hspa8 protein, mouse
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Multienzyme Complexes
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Recombinant Fusion Proteins
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Ubiquitin
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tau Proteins
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Stub1 protein, mouse
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Ube4b protein, mouse
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Ubiquitin-Protein Ligases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex