ArticleProceedings of the National Academy of Sciences of the United States of America2011
Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 92 citations in OpenAlex.
- Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease.Journal of neurosurgery · 2014Trial
- A novel peptide-based strategy to enhance GBA1 expression for treating Parkinson's disease.NPJ Parkinson's disease · 2025Article
- Epidrug screening identifies type I PRMT inhibitors as modulators of lysosomal exocytosis and drug sensitivity in cancers.Cell death & disease · 2025Article
- Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant Secretion.Biomolecules · 2025Article
- Direct and indirect regulation of β-glucocerebrosidase by the transcription factors USF2 and ONECUT2.NPJ Parkinson's disease · 2024Article
- High-throughput screening for small-molecule stabilizers of misfolded glucocerebrosidase in Gaucher disease and Parkinson's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Review
- Lysosomal storage, impaired autophagy and innate immunity in Gaucher and Parkinson's diseases: insights for drug discovery.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Development of quantitative high-throughput screening assays to identify, validate, and optimize small-molecule stabilizers of misfolded β-glucocerebrosidase with therapeutic potential for Gaucher disease and Parkinson's disease.bioRxiv : the preprint server for biology · 2024Article
- Review
- A Brain-Penetrant Stearoyl-CoA Desaturase Inhibitor Reverses α-Synuclein Toxicity.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2022Article
- Mechanistic Insight into the Mode of Action of Acid β-Glucosidase Enhancer Ambroxol.International journal of molecular sciences · 2022Article
- Genetic variations inFrontiers in neurology · 2022Review
- TRIP12 ubiquitination of glucocerebrosidase contributes to neurodegeneration in Parkinson's disease.Neuron · 2021Article
- Central Nervous System Hemangioblastoma in a Pediatric Patient Associated With Von Hippel-Lindau Disease: A Case Report and Literature Review.Frontiers in oncology · 2021Review
- Review
- Biological and clinical impact of central nervous system hemangioblastomas in Chinese patients with von Hippel-Lindau disease: implications for treatment.Hereditary cancer in clinical practice · 2020Article
- Small Molecule Chaperones for the Treatment of Gaucher Disease andFrontiers in cell and developmental biology · 2020Review
- Quantitating the epigenetic transformation contributing to cholesterol homeostasis using Gaussian process.Nature communications · 2019Article
- Glucocerebrosidase and its relevance to Parkinson disease.Molecular neurodegeneration · 2019Review
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Gaucher disease (GD) is caused by a spectrum of genetic mutations within the gene encoding the lysosomal enzyme glucocerebrosidase (GCase). These mutations often lead to misfolded proteins that are recognized by the unfolded protein response system and are degraded through the ubiquitin-proteasome pathway. Modulating this pathway with histone deacetylase inhibitors (HDACis) has been shown to improve protein stability in other disease settings. To identify the mechanisms involved in the regulation of GCase and determine the effects of HDACis on protein stability, we investigated the most prevalent mutations for nonneuronopathic (N370S) and neuronopathic (L444P) GD in cultured fibroblasts derived from GD patients and HeLa cells transfected with these mutations. The half-lives of mutant GCase proteins correspond to decreases in protein levels and enzymatic activity. GCase was found to bind to Hsp70, which directed the protein to TCP1 for proper folding, and to Hsp90, which directed the protein to the ubiquitin-proteasome pathway. Using a known HDACi (SAHA) and a unique small-molecule HDACi (LB-205), GCase levels increased rescuing enzymatic activity in mutant cells. The increase in the quantity of protein can be attributed to increases in protein half-life that correspond primarily with a decrease in degradation rather than an increase in chaperoned folding. HDACis reduce binding to Hsp90 and prevent subsequent ubiquitination and proteasomal degradation without affecting binding to Hsp70 or TCP1. These findings provide insight into the pathogenesis of GD and indicate a potent therapeutic potential of HDAC inhibitors for the treatment of GD and other human protein misfolding disorders.
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