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000137778 0247_ $$2doi$$a10.3233/JAD-142094
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000137778 0247_ $$2ISSN$$a1387-2877
000137778 0247_ $$2ISSN$$a1875-8908
000137778 037__ $$aDZNE-2020-04100
000137778 041__ $$aEnglish
000137778 082__ $$a610
000137778 1001_ $$0P:(DE-2719)2810958$$aSaidi, Laiq-Jan$$b0$$eFirst author
000137778 245__ $$aCarboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes.
000137778 260__ $$aAmsterdam$$bIOS Press$$c2015
000137778 264_1 $$2Crossref$$3print$$bIOS Press$$c2015-02-06
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000137778 520__ $$aOne of the hallmarks of Alzheimer's disease is the formation of neurofibrillary tangles, intracellular aggregates of hyperphosphorylated, mislocalized tau protein, which are associated with neuronal loss. Changes in tau are known to impair cellular transport (including that of mitochondria) and are associated with cell death in cell culture and mouse models of tauopathy. Thus clearing pathological forms of tau from cells is a key therapeutic strategy. One critical modulator in the degradation and clearance of misfolded proteins is the co-chaperone CHIP (Carboxy terminus Hsp70 interacting Protein), which is known to play a role in refolding and clearance of hyperphosphorylated tau. Here, we tested the hypothesis that CHIP could ameliorate pathological changes associated with tau. We find that co-expressing CHIP with full-length tau, tau truncated at D421 mimicking caspase cleavage, or the short tauRDΔK280 tau construct containing only the tau repeat domain with a tauopathy mutation, decreases tau protein levels in human H4 neuroglioma cells in a manner dependent on the Hsp70-binding TPR domain of CHIP. The observed reduction in tau levels by CHIP is associated with a decrease of tau phosphorylation and reduced levels of cleaved Caspase 3 indicating that CHIP plays an important role in preventing tau-induced pathological changes. Furthermore, tau-associated mitochondrial transport deficits are rescued by CHIP co-expression in H4 cells. Together, these data suggest that the co-chaperone CHIP can rescue the pathological effects of tau, and indicate that other diseases of protein misfolding and accumulation may also benefit from CHIP upregulation.
000137778 536__ $$0G:(DE-HGF)POF3-342$$a342 - Disease Mechanisms and Model Systems (POF3-342)$$cPOF3-342$$fPOF III$$x0
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000137778 650_7 $$2NLM Chemicals$$aHSP70 Heat-Shock Proteins
000137778 650_7 $$2NLM Chemicals$$atau Proteins
000137778 650_7 $$0147336-22-9$$2NLM Chemicals$$aGreen Fluorescent Proteins
000137778 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aSTUB1 protein, human
000137778 650_7 $$0EC 2.3.2.27$$2NLM Chemicals$$aUbiquitin-Protein Ligases
000137778 650_7 $$0EC 3.4.22.-$$2NLM Chemicals$$aCaspase 3
000137778 650_2 $$2MeSH$$aCaspase 3: pharmacology
000137778 650_2 $$2MeSH$$aCell Line, Tumor
000137778 650_2 $$2MeSH$$aCell Proliferation: genetics
000137778 650_2 $$2MeSH$$aGene Expression Regulation: drug effects
000137778 650_2 $$2MeSH$$aGene Expression Regulation: genetics
000137778 650_2 $$2MeSH$$aGreen Fluorescent Proteins: genetics
000137778 650_2 $$2MeSH$$aGreen Fluorescent Proteins: metabolism
000137778 650_2 $$2MeSH$$aHSP70 Heat-Shock Proteins: genetics
000137778 650_2 $$2MeSH$$aHSP70 Heat-Shock Proteins: metabolism
000137778 650_2 $$2MeSH$$aHumans
000137778 650_2 $$2MeSH$$aMitochondria: metabolism
000137778 650_2 $$2MeSH$$aMutation: genetics
000137778 650_2 $$2MeSH$$aNeuroblastoma: pathology
000137778 650_2 $$2MeSH$$aProtein Binding: drug effects
000137778 650_2 $$2MeSH$$aTransfection
000137778 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: genetics
000137778 650_2 $$2MeSH$$aUbiquitin-Protein Ligases: metabolism
000137778 650_2 $$2MeSH$$atau Proteins: genetics
000137778 650_2 $$2MeSH$$atau Proteins: metabolism
000137778 7001_ $$0P:(DE-HGF)0$$aPolydoro, Manuela$$b1
000137778 7001_ $$0P:(DE-HGF)0$$aKay, Kevin R$$b2
000137778 7001_ $$0P:(DE-HGF)0$$aSanchez, Laura$$b3
000137778 7001_ $$0P:(DE-2719)2541658$$aMandelkow, Eva-Maria$$b4
000137778 7001_ $$0P:(DE-HGF)0$$aHyman, Bradley T$$b5
000137778 7001_ $$0P:(DE-HGF)0$$aSpires-Jones, Tara L$$b6$$eCorresponding author
000137778 77318 $$2Crossref$$3journal-article$$a10.3233/jad-142094$$b : IOS Press, 2015-02-06$$n3$$p937-947$$tJournal of Alzheimer's Disease$$v44$$x1875-8908$$y2015
000137778 773__ $$0PERI:(DE-600)2070772-1$$a10.3233/JAD-142094$$gVol. 44, no. 3, p. 937 - 947$$n3$$p937-947$$q44:3<937 - 947$$tJournal of Alzheimer's disease$$v44$$x1875-8908$$y2015
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000137778 9141_ $$y2015
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