The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

Dickey, Chad A.; Kamal, Adeela; Lundgren, Karen; Klosak, Natalia; Bailey, Rachel M.; Dunmore, Judith; Ash, Peter E.A.; Shoraka, Sareh; Zlatković, Jelena; Eckman, Christopher B.; Patterson, Cam; Dickson, Dennis W.; Nahman, N. S.; Hutton, Michael; Burrows, Francis; Petrucelli, Leonard

doi:10.1172/jci29715

Cited by 562 publications

(657 citation statements)

References 50 publications

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“…Proteins such as hsp70 and their binding partners (e.g., CHIP) are thought to control the level of soluble Tau and thus help to prevent aggregation in a phosphorylation-dependent manner (Shimura et al 2004a,b;Dickey et al 2007;Petrucelli et al 2004). The binding site has been mapped to the motif VQIVYK, the same as the site responsible for b-structure and aggregation (Sarkar et al 2008).…”

Section: Fkbp52mentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

663

633

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Tau represents the subunit protein of one of the major hallmarks of Alzheimer disease (AD), the neurofibrillary tangles, and is therefore of major interest as an indicator of disease mechanisms. Many of the unusual properties of Tau can be explained by its nature as a natively unfolded protein. Examples are the large number of structural conformations and biochemical modifications ( phosphorylation, proteolysis, glycosylation, and others), the multitude of interaction partners (mainly microtubules, but also other cytoskeletal proteins, kinases, and phosphatases, motor proteins, chaperones, and membrane proteins). The pathological aggregation of Tau is counterintuitive, given its high solubility, but can be rationalized by short hydrophobic motifs forming b structures. The aggregation of Tau is toxic in cell and animal models, but can be reversed by suppressing expression or by aggregation inhibitors. This review summarizes some of the structural, biochemical, and cell biological properties of Tau and Tau fibers. Further aspects of Tau as a diagnostic marker and therapeutic target, its involvement in other Tau-based diseases, and its histopathology are covered by other chapters in this volume.

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Section: Fkbp52mentioning

confidence: 99%

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Mandelkow

2012

Cold Spring Harbor Perspectives in Medicine

663

633

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“…Hyperphosphorylated tau is a client of the Hsc/Hsp70 and Hsp90 chaperone network and is targeted for proteasomal degradation by CHIP (Shimura et al, 2004;Dickey et al, 2007). An Hsp90 inhibitor that is able to cross the blood-brain barrier (e.g., EC102) induces tau degradation through CHIP-mediated CAP in cellbased assays and facilitates the disposal of aberrant tau in a transgenic mouse model of tauopathy (Dickey et al, 2007). …”

Section: Cap: Chaperone-assisted Proteasomal Degradationmentioning

confidence: 99%

Chaperone-assisted degradation: multiple paths to destruction

Kettern

Dreiseidler

Tawo³

et al. 2010

Biological Chemistry

151

155

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Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP ( haperone-ssisted roteasomal degradac a p tion), CASA ( haperone-ssisted elective utophagy), and c a s a CMA ( haperone-ediated utophagy). Within these pathc m a ways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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“…Hsc70-mediated stabilization of tau levels may be relevant to tauopathies, as high levels of Hsc70 are found in brains of AD patients relative to other Hsp70 isoforms (30). Compounds that inhibit Hsp90 and Hsp70 family proteins reduce tau levels (6,11,(31)(32)(33) and rescue synaptic plasticity defects in tauopathy mouse models (33). Based on this evidence, we sought to determine why Hsc70 and tau are so intimately involved with each other and perhaps determine the most effective way to exploit this interaction for therapeutic intervention to treat tauopathies.…”

Section: Introductionmentioning

confidence: 99%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins

Cited by 562 publications

References 50 publications

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

Chaperone-assisted degradation: multiple paths to destruction

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

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