title: Involvement of endoplasmic reticulum stress in tauopathy.
abstract: Tauopathy is a pathological condition with an abnormal intracellular accumulation of tau protein in neurons and glias, which is a feature of Alzheimer's disease (AD) as well as frontotemporal lobar degenerations (FTLD). Recent reports showed that tauopathy occupies an important position for pathological process of dementia generally. Previously, we reported that endoplasmic reticulum (ER) stress has an influence on the onset of AD. In addition, some reports on brain autopsy findings suggest that ER stress is associated with AD and tauopathy. However, the mechanism underlying the association between ER stress and tauopathy is still unknown. Here, we show that ER stress, induced by glucose deprivation or chemicals, increases total endogenous tau protein in cultured neurons and primary cultured neurons. Under ER stress, no significant differences were observed in the transcription of tau, and no differences were observed in the translation of tau with or without the 5'-untranslated region (5'UTR) of tau. In contrast, the degradation rate of tau was decreased by 20% under ER stress. ER stress reduced the binding between tau and carboxyl terminus of Hsc70-interacting protein (CHIP), ubiquitin E3 ligase for tau. These results suggest that ER stress increases total tau protein and its mechanism is due to the decrease in the binding between tau and CHIP, which delays the degradation of tau protein through the ubiquitin-proteasome pathway. This mechanism may provide clue to treatment for tauopathy.
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, D3 2-2 Yamadaoka, Suita City, Osaka 565-0871, Japan.
authors.forename: Yukako
authors.initials: Y
authors.lastname: Sakagami
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Tanimukai
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kanayama
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Omi
authors.forename: Kikumi
authors.initials: K
authors.lastname: Horiguchi
authors.forename: Masayasu
authors.initials: M
authors.lastname: Okochi
authors.forename: Kazunori
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006801:Humans; D009474:Neurons / Q000378:metabolism*; D000071701:Regulatory Factor X Transcription Factors; D024801:Tauopathies / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D016875:tau Proteins / Q000096:biosynthesis*
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D016875:tau Proteins; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases