ArticleACS chemical biology2012
Pharmacological tuning of heat shock protein 70 modulates polyglutamine toxicity and aggregation.
Article in ACS chemical biology, 2012. 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.
- 1-Mesityl-3-(3-Sulfonatopropyl) Imidazolium Protects Against Oxidative Stress and Delays Proteotoxicity inFrontiers in pharmacology · 2022Article
- Targeting Hsp70 facilitated protein quality control for treatment of polyglutamine diseases.Cellular and molecular life sciences : CMLS · 2020Review
- Inhibitors and chemical probes for molecular chaperone networks.The Journal of biological chemistry · 2019Review
- Human DnaJB6 Antiamyloid Chaperone Protects Yeast from Polyglutamine Toxicity Separately from Spatial Segregation of Aggregates.Molecular and cellular biology · 2018Article
- Protein-Protein Interactions in the Molecular Chaperone Network.Accounts of chemical research · 2018Review
- Pathways of cellular proteostasis in aging and disease.The Journal of cell biology · 2018Review
- Modulation of Molecular Chaperones in Huntington's Disease and Other Polyglutamine Disorders.Molecular neurobiology · 2017Review
- HMBA is a putative HSP70 activator stimulating HEXIM1 expression that is down-regulated by estrogen.The Journal of steroid biochemistry and molecular biology · 2017Article
- Candida albicans Is Resistant to Polyglutamine Aggregation and Toxicity.G3 (Bethesda, Md.) · 2017Article
- Multiple discrete soluble aggregates influence polyglutamine toxicity in a Huntington's disease model system.Scientific reports · 2016Article
- A current pharmacologic agent versus the promise of next generation therapeutics to ameliorate protein misfolding and/or aggregation diseases.Current opinion in chemical biology · 2016Review
- Targeting Allosteric Control Mechanisms in Heat Shock Protein 70 (Hsp70).Current topics in medicinal chemistry · 2016Review
- Targeting protein aggregation for the treatment of degenerative diseases.Nature reviews. Drug discovery · 2015Review
- High-throughput screen of natural product extracts in a yeast model of polyglutamine proteotoxicity.Chemical biology & drug design · 2014Article
- Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias.Cerebellum (London, England) · 2014Article
- Aggregation formation in the polyglutamine diseases: protection at a cost?Molecules and cells · 2013Review
- 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.ACS chemical neuroscience · 2013Article
- Identification of key hinge residues important for nucleotide-dependent allostery in E. coli Hsp70/DnaK.PLoS computational biology · 2013Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.
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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.