Journal Article

DZNE-2020-04100

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Carboxy terminus heat shock protein 70 interacting protein reduces tau-associated degenerative changes.

Saidi, L.-J. (First author)DZNE* ; Polydoro, M. ; Kay, K. R. ; Sanchez, L. ; Mandelkow, E.-M.DZNE* ; Hyman, B. T. ; Spires-Jones, T. L. (Corresponding author)

2015
IOS Press Amsterdam

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Please use a persistent id in citations: doi:10.3233/JAD-142094

Abstract: One 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.

Keyword(s): Caspase 3: pharmacology (MeSH) ; Cell Line, Tumor (MeSH) ; Cell Proliferation: genetics (MeSH) ; Gene Expression Regulation: drug effects (MeSH) ; Gene Expression Regulation: genetics (MeSH) ; Green Fluorescent Proteins: genetics (MeSH) ; Green Fluorescent Proteins: metabolism (MeSH) ; HSP70 Heat-Shock Proteins: genetics (MeSH) ; HSP70 Heat-Shock Proteins: metabolism (MeSH) ; Humans (MeSH) ; Mitochondria: metabolism (MeSH) ; Mutation: genetics (MeSH) ; Neuroblastoma: pathology (MeSH) ; Protein Binding: drug effects (MeSH) ; Transfection (MeSH) ; Ubiquitin-Protein Ligases: genetics (MeSH) ; Ubiquitin-Protein Ligases: metabolism (MeSH) ; tau Proteins: genetics (MeSH) ; tau Proteins: metabolism (MeSH) ; HSP70 Heat-Shock Proteins ; tau Proteins ; Green Fluorescent Proteins ; STUB1 protein, human ; Ubiquitin-Protein Ligases ; Caspase 3

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Contributing Institute(s):

1. Cell and Animal Models of Neurodegeneration (AG Mandelkow 2)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2015

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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Linked articles:

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Dissertation / PhD Thesis Saidi, L. J.DZNE*
Carboxy terminus heat shock protein 70 interacting protein (CHIP) reduces Tau-associated degenerative changes.
50 pages, 17 figures (2013)2013 = Dissertation, Universität zu Köln, 2013 BibTeX | EndNote: XML, Text | RIS

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