Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics.
Fontaine SN
,
Martin MD
,
Akoury E
,
Assimon VA
,
Borysov S
,
Nordhues BA
,
Sabbagh JJ
,
Cockman M
,
Gestwicki JE
,
Zweckstetter M
,
Dickey CA
.
???displayArticle.abstract???
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.
Abisambra,
Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
2013, Pubmed
Abisambra,
Allosteric heat shock protein 70 inhibitors rapidly rescue synaptic plasticity deficits by reducing aberrant tau.
2013,
Pubmed
Agueli,
A constitutive 70 kDa heat-shock protein is localized on the fibres of spindles and asters at metaphase in an ATP-dependent manner: a new chaperone role is proposed.
2001,
Pubmed
Ahmad,
Identification of a protein altered in mutants resistant to microtubule inhibitors as a member of the major heat shock protein (hsp70) family.
1990,
Pubmed
Akihisa,
4-Hydroxyderricin from Angelica keiskei roots induces caspase-dependent apoptotic cell death in HL60 human leukemia cells.
2011,
Pubmed
Ansar,
A non-toxic Hsp90 inhibitor protects neurons from Abeta-induced toxicity.
2007,
Pubmed
Baquero,
Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts.
2011,
Pubmed
Breuzard,
Molecular mechanisms of Tau binding to microtubules and its role in microtubule dynamics in live cells.
2013,
Pubmed
Chen,
Hsp90 chaperone inhibitor 17-AAG attenuates Aβ-induced synaptic toxicity and memory impairment.
2014,
Pubmed
Choi,
Human microtubule-associated-protein tau regulates the number of protofilaments in microtubules: a synchrotron x-ray scattering study.
2009,
Pubmed
Colvin,
Hsp70-Bag3 interactions regulate cancer-related signaling networks.
2014,
Pubmed
Dickey,
The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins.
2007,
Pubmed
Dou,
Chaperones increase association of tau protein with microtubules.
2003,
Pubmed
Fischer,
Structural and microtubule binding properties of tau mutants of frontotemporal dementias.
2007,
Pubmed
Flaherty,
Structural basis of the 70-kilodalton heat shock cognate protein ATP hydrolytic activity. II. Structure of the active site with ADP or ATP bound to wild type and mutant ATPase fragment.
1994,
Pubmed
Gache,
Identification of proteins binding the native tubulin dimer.
2005,
Pubmed
Gogolla,
Staining protocol for organotypic hippocampal slice cultures.
2006,
Pubmed
Goode,
Functional interactions between the proline-rich and repeat regions of tau enhance microtubule binding and assembly.
1997,
Pubmed
Hasegawa,
Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly.
1998,
Pubmed
Hughes,
A microtubule interactome: complexes with roles in cell cycle and mitosis.
2008,
Pubmed
Iwasaki,
BAG3 regulates motility and adhesion of epithelial cancer cells.
2007,
Pubmed
Jinwal,
Chemical manipulation of hsp70 ATPase activity regulates tau stability.
2009,
Pubmed
Jinwal,
Hsc70 rapidly engages tau after microtubule destabilization.
2010,
Pubmed
,
Xenbase
Jinwal,
Imbalance of Hsp70 family variants fosters tau accumulation.
2013,
Pubmed
,
Xenbase
Johnson,
Widespread τ and amyloid-β pathology many years after a single traumatic brain injury in humans.
2012,
Pubmed
Kang,
Heat shock protein 70 inhibitors. 1. 2,5'-thiodipyrimidine and 5-(phenylthio)pyrimidine acrylamides as irreversible binders to an allosteric site on heat shock protein 70.
2014,
Pubmed
Karagöz,
Hsp90-Tau complex reveals molecular basis for specificity in chaperone action.
2014,
Pubmed
Kityk,
Structure and dynamics of the ATP-bound open conformation of Hsp70 chaperones.
2012,
Pubmed
Koren,
Rhodacyanine derivative selectively targets cancer cells and overcomes tamoxifen resistance.
2012,
Pubmed
Koya,
MKT-077, a novel rhodacyanine dye in clinical trials, exhibits anticarcinoma activity in preclinical studies based on selective mitochondrial accumulation.
1996,
Pubmed
Li,
Tau proteins expressions in advanced breast cancer and its significance in taxane-containing neoadjuvant chemotherapy.
2013,
Pubmed
Li,
Analogs of the Allosteric Heat Shock Protein 70 (Hsp70) Inhibitor, MKT-077, as Anti-Cancer Agents.
2013,
Pubmed
Ma,
Dual targeting of heat shock proteins 90 and 70 promotes cell death and enhances the anticancer effect of chemotherapeutic agents in bladder cancer.
2014,
Pubmed
Mayer,
Multistep mechanism of substrate binding determines chaperone activity of Hsp70.
2000,
Pubmed
Miyata,
Synthesis and initial evaluation of YM-08, a blood-brain barrier permeable derivative of the heat shock protein 70 (Hsp70) inhibitor MKT-077, which reduces tau levels.
2013,
Pubmed
Modica-Napolitano,
Selective damage to carcinoma mitochondria by the rhodacyanine MKT-077.
1996,
Pubmed
Panda,
Differential regulation of microtubule dynamics by three- and four-repeat tau: implications for the onset of neurodegenerative disease.
2003,
Pubmed
Parker,
Microtubules and their role in cellular stress in cancer.
2014,
Pubmed
Pentheroudakis,
Gene expression of estrogen receptor, progesterone receptor and microtubule-associated protein Tau in high-risk early breast cancer: a quest for molecular predictors of treatment benefit in the context of a Hellenic Cooperative Oncology Group trial.
2009,
Pubmed
Pusztai,
Evaluation of microtubule-associated protein-Tau expression as a prognostic and predictive marker in the NSABP-B 28 randomized clinical trial.
2009,
Pubmed
Putcha,
Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity.
2010,
Pubmed
Rattner,
hsp70 is localized to the centrosome of dividing HeLa cells.
1991,
Pubmed
Rauch,
Binding of human nucleotide exchange factors to heat shock protein 70 (Hsp70) generates functionally distinct complexes in vitro.
2014,
Pubmed
Rodina,
Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer.
2007,
Pubmed
Rodina,
Identification of an allosteric pocket on human hsp70 reveals a mode of inhibition of this therapeutically important protein.
2013,
Pubmed
Rousaki,
Allosteric drugs: the interaction of antitumor compound MKT-077 with human Hsp70 chaperones.
2011,
Pubmed
Sanchez,
Assembly and bundling of marginal band microtubule protein: role of tau.
1994,
Pubmed
Sarkar,
Two motifs within the tau microtubule-binding domain mediate its association with the hsc70 molecular chaperone.
2008,
Pubmed
Schlecht,
Functional analysis of Hsp70 inhibitors.
2013,
Pubmed
Sconzo,
Constitutive hsp70 is essential to mitosis during early cleavage of Paracentrotus lividus embryos: the blockage of constitutive hsp70 impairs mitosis.
1999,
Pubmed
Smoter,
Tau protein as a potential predictive marker in epithelial ovarian cancer patients treated with paclitaxel/platinum first-line chemotherapy.
2013,
Pubmed
Sánchez,
Binding of heat-shock protein 70 (hsp70) to tubulin.
1994,
Pubmed
Taldone,
Heat shock protein 70 inhibitors. 2. 2,5'-thiodipyrimidines, 5-(phenylthio)pyrimidines, 2-(pyridin-3-ylthio)pyrimidines, and 3-(phenylthio)pyridines as reversible binders to an allosteric site on heat shock protein 70.
2014,
Pubmed
Tikoo,
Treatment of ras-induced cancers by the F-actin-bundling drug MKT-077.
2000,
Pubmed
Wadhwa,
Selective toxicity of MKT-077 to cancer cells is mediated by its binding to the hsp70 family protein mot-2 and reactivation of p53 function.
2000,
Pubmed
Weingarten,
A protein factor essential for microtubule assembly.
1975,
Pubmed
Young,
Pathways of chaperone-mediated protein folding in the cytosol.
2004,
Pubmed
Yuan,
Tubulin and neurofilament proteins are transported differently in axons of chicken motoneurons.
2000,
Pubmed
Zitzmann,
Potent antitumor activity of the novel HSP90 inhibitors AUY922 and HSP990 in neuroendocrine carcinoid cells.
2013,
Pubmed
