ArticleThe Journal of biological chemistry2012
A screen for enhancers of clearance identifies huntingtin as a heat shock protein 90 (Hsp90) client protein.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
54 citing papers in PubMed, 88 citations in OpenAlex.
- Investigating the potential mechanism of bisphenols on neurodegeneration through network toxicology and molecular docking.NAM journal · 2025Article
- A single-nuclei paired multiomic analysis of the human midbrain reveals age- and Parkinson's disease-associated glial changes.Nature aging · 2024Article
- Mutant-Huntingtin Molecular Pathways Elucidate New Targets for Drug Repurposing.International journal of molecular sciences · 2023Review
- Heat shock factor HSF1 regulates BDNF gene promoters upon acute stress in the hippocampus, together with pCREB.Journal of neurochemistry · 2023Article
- HSF1 and Its Role in Huntington's Disease Pathology.Advances in experimental medicine and biology · 2023Review
- Pathogenesis of Huntington's Disease: An Emphasis on Molecular Pathways and Prevention by Natural Remedies.Brain sciences · 2022Review
- Differential roles for DNAJ isoforms in HTT-polyQ and FUS aggregation modulation revealed by chaperone screens.Nature communications · 2022Article
- Mutant Huntingtin Protein Interaction Map Implicates Dysregulation of Multiple Cellular Pathways in Neurodegeneration of Huntington's Disease.Journal of Huntington's disease · 2022Article
- Small molecule splicing modifiers with systemic HTT-lowering activity.Nature communications · 2021Article
- Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin.Journal of personalized medicine · 2021Review
- The role and therapeutic potential of Hsp90, Hsp70, and smaller heat shock proteins in peripheral and central neuropathies.Medicinal research reviews · 2021Review
- Taming the Huntington's Disease Proteome: What Have We Learned?Journal of Huntington's disease · 2021Review
- Osmolytes dynamically regulate mutant Huntingtin aggregation and CREB function in Huntington's disease cell models.Scientific reports · 2020Article
- Approaches to develop therapeutics to treat frontotemporal dementia.Neuropharmacology · 2020Review
- Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington's Disease.Neuroscience bulletin · 2019Article
- Hsp90 and Its Co-Chaperones in Neurodegenerative Diseases.International journal of molecular sciences · 2019Review
- Quality Control in Huntington's Disease: a Therapeutic Target.Neurotoxicity research · 2019Review
- Genetic Regulation of Neuronal Progranulin Reveals a Critical Role for the Autophagy-Lysosome Pathway.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Targeting the proteostasis network in Huntington's disease.Ageing research reviews · 2019Review
- Therapeutic Potential of the Hsp90/Cdc37 Interaction in Neurodegenerative Diseases.Frontiers in neuroscience · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Mechanisms to reduce the cellular levels of mutant huntingtin (mHtt) provide promising strategies for treating Huntington disease (HD). To identify compounds enhancing the degradation of mHtt, we performed a high throughput screen using a hippocampal HN10 cell line expressing a 573-amino acid mHtt fragment. Several hit structures were identified as heat shock protein 90 (Hsp90) inhibitors. Cell treatment with these compounds reduced levels of mHtt without overt toxic effects as measured by time-resolved Förster resonance energy transfer assays and Western blots. To characterize the mechanism of mHtt degradation, we used the potent and selective Hsp90 inhibitor NVP-AUY922. In HdhQ150 embryonic stem (ES) cells and in ES cell-derived neurons, NVP-AUY922 treatment substantially reduced soluble full-length mHtt levels. In HN10 cells, Hsp90 inhibition by NVP-AUY922 enhanced mHtt clearance in the absence of any detectable Hsp70 induction. Furthermore, inhibition of protein synthesis with cycloheximide or overexpression of dominant negative heat shock factor 1 (Hsf1) in HdhQ150 ES cells attenuated Hsp70 induction but did not affect NVP-AUY922-mediated mHtt clearance. Together, these data provided evidence that direct inhibition of Hsp90 chaperone function was crucial for mHtt degradation rather than heat shock response induction and Hsp70 up-regulation. Co-immunoprecipitation experiments revealed a physical interaction of mutant and wild-type Htt with the Hsp90 chaperone. Hsp90 inhibition disrupted the interaction and induced clearance of Htt through the ubiquitin-proteasome system. Our data suggest that Htt is an Hsp90 client protein and that Hsp90 inhibition may provide a means to reduce mHtt in HD.
Indexed as
Identifiers
What OpenQuestion holds
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.