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U‐box protein carboxyl terminus of Hsc70‐interacting protein (CHIP) mediates poly‐ubiquitylation preferentially on four‐repeat Tau and is involved in neurodegeneration of tauopathy
Author(s) -
Hatakeyama Shigetsugu,
Matsumoto Masaki,
Kamura Takumi,
Murayama Miyuki,
Chui DuHua,
Planel Emmanuel,
Takahashi Ryosuke,
Nakayama Keiichi I.,
Takashima Akihiko
Publication year - 2004
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2004.02713.x
Subject(s) - tauopathy , progressive supranuclear palsy , neurodegeneration , tau protein , ubiquitin , ubiquitin ligase , frontotemporal dementia , microbiology and biotechnology , microtubule , microtubule associated protein , chemistry , biology , biochemistry , alzheimer's disease , dementia , medicine , genetics , atrophy , gene , disease
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.