Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain

Thirstrup, Kenneth; Sotty, Florence; Montezinho, L.C.; Badolo, Lassina; Thougaard, Annemette; Kristjánsson, Maj; Jensen, Tommy R.; Watson, Stephen P.; Nielsen, Søren

doi:10.1016/j.phrs.2015.12.028

Cited by 18 publications

(13 citation statements)

References 32 publications

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“…Thirstrup and coworkers noted that HSP90 inhibition in both their study and Chen's 17-AAG study alleviated synaptic impairments well within 24 h and suggested that HSP90 inhibition may work independent of tau clearance (Thirstrup et al 2015). Unfortunately, the toxicity of conventional HSP90 inhibitors limits their role in the clinical setting (Zhou et al 2013).…”

Section: Background: Synapse Formation and Maturationmentioning

confidence: 98%

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

Hooper

Durham

Török

et al. 2016

Cell Stress and Chaperones

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Networks of neuronal synapses are the fundamental basis for making and retaining memory. Reduced synapse number and quality correlates with loss of memory in dementia. Heat shock factor 1 (HSF1), the major transcription factor regulating expression of heat shock genes, plays a central role in proteostasis, in establishing and sustaining synaptic fidelity and function, and in memory consolidation. Support for this thesis is based on these observations: (1) heat shock induces improvements in synapse integrity and memory consolidation; (2) synaptic depolarization activates HSF1; (3) activation of HSF1 alone (independent of the canonical heat shock response) augments formation of essential synaptic elementsneuroligands, vesicle transport, synaptic scaffolding proteins, lipid rafts, synaptic spines, and axodendritic synapses; (4) HSF1 coalesces and activates memory receptors in the postsynaptic dendritic spine; (5) huntingtin or α-synuclein accumulation lowers HSF1 while HSF1 lowers huntingtin and α-synuclein aggregation-a potential vicious cycle; and (6) HSF1 agonists (including physical activity) can improve cognitive function in dementia models. Thus, via direct gene expression of synaptic elements, production of HSPs that assure high protein fidelity, and activation of other neuroprotective signaling pathways, HSF1 agonists could provide breakthrough therapy for dementia-associated disease.

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Section: Background: Synapse Formation and Maturationmentioning

confidence: 98%

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

Hooper

Durham

Török

et al. 2016

Cell Stress and Chaperones

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“…The activities of Hsp90 and Hsp70 are tightly linked via HSF1. Hsp90 inhibitors typically activate HSF1, which in turn induces Hsp70 [68]. A variety of small molecule drugs have been developed that inhibit Hsp90, activate Hsp70, or both, and have been shown to reduce the formation of disease protein aggregates, reduce cellular toxicity, and improve neurological phenotypes in cellular and animal models of SBMA, HD, PD, and AD [62, 67, 69–71].…”

Section: Therapeutic Targetsmentioning

confidence: 99%

Protein misfolding in neurodegenerative diseases: implications and strategies

Sweeney

Park²,

Baumann

et al. 2017

Transl Neurodegener

508

307

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A hallmark of neurodegenerative proteinopathies is the formation of misfolded protein aggregates that cause cellular toxicity and contribute to cellular proteostatic collapse. Therapeutic options are currently being explored that target different steps in the production and processing of proteins implicated in neurodegenerative disease, including synthesis, chaperone-assisted folding and trafficking, and degradation via the proteasome and autophagy pathways. Other therapies, like mTOR inhibitors and activators of the heat shock response, can rebalance the entire proteostatic network. However, there are major challenges that impact the development of novel therapies, including incomplete knowledge of druggable disease targets and their mechanism of action as well as a lack of biomarkers to monitor disease progression and therapeutic response. A notable development is the creation of collaborative ecosystems that include patients, clinicians, basic and translational researchers, foundations and regulatory agencies to promote scientific rigor and clinical data to accelerate the development of therapies that prevent, reverse or delay the progression of neurodegenerative proteinopathies.

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“…Other Hsp90 inhibitors or modulators were recently investigated (see Figure 10 ). Reversal of synaptic impairments in a rTg4510 transgenic AD mouse model was obtained with compound NVP-HSP990 which has a high Hsp70 induction capacity and is probably able to induce Tau clearance [ 135 ]. Pochoxime C (OS47720), a CNS-permeable and non-toxic Hsp90 inhibiting compound, restores synaptic dysfunction and memory loss in vivo in a Tg2576 mice AD model [ 136 ].…”

Section: Hsp90mentioning

confidence: 99%

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

Campanella

Pace

Bavisotto

et al. 2018

IJMS

133

104

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Among diseases whose cure is still far from being discovered, Alzheimer’s disease (AD) has been recognized as a crucial medical and social problem. A major issue in AD research is represented by the complexity of involved biochemical pathways, including the nature of protein misfolding, which results in the production of toxic species. Considering the involvement of (mis)folding processes in AD aetiology, targeting molecular chaperones represents a promising therapeutic perspective. This review analyses the connection between AD and molecular chaperones, with particular attention toward the most important heat shock proteins (HSPs) as representative components of the human chaperome: Hsp60, Hsp70 and Hsp90. The role of these proteins in AD is highlighted from a biological point of view. Pharmacological targeting of such HSPs with inhibitors or regulators is also discussed.

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Linking HSP90 target occupancy to HSP70 induction and efficacy in mouse brain

Cited by 18 publications

References 32 publications

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

The central role of heat shock factor 1 in synaptic fidelity and memory consolidation

Protein misfolding in neurodegenerative diseases: implications and strategies

Heat Shock Proteins in Alzheimer’s Disease: Role and Targeting

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