Isoform-selective Genetic Inhibition of Constitutive Cytosolic Hsp70 Activity Promotes Client Tau Degradation Using an Altered Co-chaperone Complement

Fontaine, Sarah N.; Rauch, Jennifer N.; Nordhues, Bryce A.; Assimon, Victoria A.; Stothert, Andrew R.; Jinwal, Umesh K.; Sabbagh, Jonathan J.; Chang, Lyra; Stevens, Stanley M.; Zuiderweg, Erik R. P.; Gestwicki, Jason E.; Dickey, Chad A.

doi:10.1074/jbc.m115.637595

Cited by 41 publications

(39 citation statements)

References 72 publications

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“…We considered this experiment to be important because the selectivity of small molecules in cells is often uncertain, so combining small molecules with genetics is a way to independently assess the model. As mentioned previously, a point mutant in Hsc70, E175S, had recently been shown to stabilize the Hsc70-tau interaction and lead to enhanced turnover (Fontaine et al, 2015). This result is consistent with the prediction, but to further interrogate this system we mutated residues in JG-48's binding site on Hsc70 (see Fig.…”

Section: Resultsmentioning

confidence: 93%

“…Consistent with the ELISA, JG-48 enhanced binding of Hsp70 to tau, by ∼ 4-fold (Figure 5B). Interestingly, treatment with JG-48 did not change the amount of Hsc70 that was co-immunoprecipitated with tau (Figure 5B), perhaps because of competition between these chaperones for binding (Fontaine et al, 2015). …”

Section: Resultsmentioning

confidence: 99%

“…HeLa C3 cells were stably transfected with V5-4R0N tau as previously described (Fontaine et al, 2015). Cells were cultured in supplemented Opti-MEM media.…”

Section: Methodsmentioning

confidence: 99%

“…Differences in the ability of Hsc70 and Hsp70 to recruit CHIP are surprising because they are more than 85% identical and they have the same affinity for CHIP in vitro (Smith et al, 2013). However, over-expression of a dominant negative form of Hsc70 has recently been found to enhanced turnover of tau (Fontaine et al, 2015), suggesting that Hsc70 and Hsp70 are both capable of directing tau to the degradation pathway under some conditions. Together, these results show a close relationship between Hsp70s and tau homeostasis, but the molecular mechanisms are not clear.…”

Section: Introductionmentioning

confidence: 99%

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Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

Young

Rauch

Assimon

et al. 2016

Cell Chemical Biology

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Summary Heat shock protein 70 (Hsp70) is a chaperone that normally scans the proteome and initiates the turnover of some proteins (termed “clients”) by linking them to the degradation pathways. This activity is critical to normal protein homeostasis, yet it appears to fail in diseases associated with abnormal protein accumulation. It is not clear why Hsp70 promotes client degradation under some conditions, while sparing that protein under others. Here, we use a combination of chemical biology and genetics strategies to systematically perturb the affinity of Hsp70 for the model client, tau. This approach revealed that tight complexes between Hsp70 and tau are associated with enhanced turnover while transient interactions favored tau retention. These results suggest that client affinity is one important parameter governing Hsp70-mediated quality control.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

“…HeLa C3 cells were stably transfected with V5-4R0N tau as previously described (Fontaine et al, 2015). Cells were cultured in supplemented Opti-MEM media.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stabilizing the Hsp70-Tau Complex Promotes Turnover in Models of Tauopathy

Young

Rauch

Assimon

et al. 2016

Cell Chemical Biology

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“…Additional treatment approaches have included: aggregation inhibition using various types of small molecules (O’Leary et al, 2010); degradation of aggregates and clearance by enhancing metabolic processes such as those initiated by heat shock proteins (HSP), the UPS and/or autophagy (Fontaine et al, 2015); direct stabilization of microtubules using paclitaxel, EpoD, or other known microtubule stabilizing agents (Brunden et al, 2010); proteolysis or use of proteases and other methods of aggregate degradation (Guerrero-Munoz et al, 2014) (Utton et al, 2005, Oddo et al, 2009, Gotz et al, 2012, Himmelstein et al, 2012, Mandelkow and Mandelkow, 2012, Wolfe, 2012, Guerrero-Munoz et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

Tau-Directed Immunotherapy: A Promising Strategy for Treating Alzheimer’s Disease and Other Tauopathies

Schroeder

Joly‐Amado

Gordon

et al. 2015

J Neuroimmune Pharmacol

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Immunotherapy directed against tau is a promising treatment strategy for Alzheimer’s Disease (AD) and tauopathies. We review initial studies on tau-directed immunotherapy, and present data from our laboratory testing antibodies using the rTg4510 mouse model, which deposits tau in forebrain neurons. Numerous antibodies have been tested for their efficacy in treating both pathology and cognitive function, in different mouse models, by different routes of administration, and at different ages or durations. We report, here, that the conformation-specific antibody MC-1 produces some degree of improvement to both cognition and pathology in rTg4510. Pathological improvements as measured by Gallyas staining for fully formed tangles and phosphorylated tau appeared four days after intracranial injection into the hippocampus. We also examined markers for microglial activation, which did not appear impacted from treatment. Behavioral effects were noted after continuous infusion of antibodies into the lateral ventricle for approximately 2 weeks. We examined basic motor skills, which were not impacted by treatment, but did note cognitive improvements with both novel object and radial arm water maze testing. Our results support earlier reports in the initial review presented here, and collectively show promise for this strategy of treatment. The general absence of extracellular tau deposits may avoid the opsonization and phagocytosis mechanisms activated by antibodies against amyloid, and make anti tau approaches a safer method of immunotherapy for Alzheimer’s disease.

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