ArticleFrontiers in molecular biosciences2018
Dihydropyridines Allosterically Modulate Hsp90 Providing a Novel Mechanism for Heat Shock Protein Co-induction and Neuroprotection.
Article in Frontiers in molecular biosciences, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.Frontiers in aging neuroscience · 2026Review
- Beyond Inhibition: Rebalancing the Hsp90 Chaperone Network as a Therapeutic Strategy for Alzheimer's Disease.Drug design, development and therapy · 2026Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- In vivo imaging of heat shock protein 90: Diagnostic tool and support for Hsp90-targeted therapy.Cell stress & chaperones · 2025Review
- The role of the FKBP51-Hsp90 complex in Alzheimer's disease: An emerging new drug target.Cell stress & chaperones · 2024Review
- Second international symposium on the chaperone code, 2023.Cell stress & chaperones · 2024Article
- Updates on Aβ Processing by Hsp90, BRICHOS, and Newly Reported Distinctive Chaperones.Biomolecules · 2023Review
- The Crystal Structure of the Hsp90-LA1011 Complex and the Mechanism by Which LA1011 May Improve the Prognosis of Alzheimer's Disease.Biomolecules · 2023Article
- Recent advances toward the development of Hsp90 C-terminal inhibitors.Bioorganic & medicinal chemistry letters · 2023Review
- Hsp90: From Cellular to Organismal Proteostasis.Cells · 2022Review
- Review
- Assay design and development strategies for finding Hsp90 inhibitors and their role in human diseases.Pharmacology & therapeutics · 2021Review
- Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?Frontiers in neuroscience · 2021Review
- Targeting microglia L-type voltage-dependent calcium channels for the treatment of central nervous system disorders.Journal of neuroscience research · 2021Review
- Allosteric Regulation of Hsp90α's Activity by Small Molecules Targeting the Middle Domain of the Chaperone.iScience · 2020Article
- Dynamically Shaping Chaperones. Allosteric Modulators of HSP90 Family as Regulatory Tools of Cell Metabolism in Neoplastic Progression.Frontiers in oncology · 2020Review
- Histamine Is an Inducer of the Heat Shock Response in SOD1-G93A Models of ALS.International journal of molecular sciences · 2019Article
- The impact of dihydropyridine derivatives on the cerebral blood flow response to somatosensory stimulation and spreading depolarization.British journal of pharmacology · 2019Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Chaperones play a pivotal role in protein homeostasis, but with age their ability to clear aggregated and damaged protein from cells declines. Tau pathology is a driver of a variety of neurodegenerative disease and in Alzheimer's disease (AD) it appears to be precipitated by the formation of amyloid-β (Aβ) aggregates. Aβ-peptide appears to trigger Tau hyperphosphorylation, formation of neurofibrillary tangles and neurotoxicity. Recently, dihydropyridine derivatives were shown to upregulate the heat shock response (HSR) and provide a neuroprotective effect in an APPxPS1 AD mouse model. The HSR response was only seen in diseased cells and consequently these compounds were defined as co-inducers since they upregulate chaperones and co-chaperones only when a pathological state is present. We show for compounds tested herein, that they target predominantly the C-terminal domain of Hsp90, but show some requirement for its middle-domain, and that binding stimulates the chaperones ATPase activity. We identify the site for LA1011 binding and confirm its identification by mutagenesis. We conclude, that binding compromises Hsp90's ability to chaperone, by modulating its ATPase activity, which consequently induces the HSR in diseased cells. Collectively, this represents the mechanism by which the normalization of neurofibrillary tangles, preservation of neurons, reduced tau pathology, reduced amyloid plaque, and increased dendritic spine density in the APPxPS1 Alzheimer's mouse model is initiated. Such dihydropyridine derivatives therefore represent potential pharmaceutical candidates for the therapy of neurodegenerative disease, such as AD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.