title: Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones.
abstract: Gaucher disease is caused by mutations of the GBA gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations often result in protein misfolding and premature degradation, but usually exert less effect on catalytic activity. In this study, we identified the molecular mechanism by which histone deacetylase inhibitors increase the quantity and activity of GCase. Specifically, these inhibitors limit the deacetylation of heat shock protein 90, resulting in less recognition of the mutant peptide and GCase degradation. These findings provide insight into a possible therapeutic strategy for Gaucher disease and other genetic disorders by modifying molecular chaperone and protein degradation pathways.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, and Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Shervin
authors.initials: S
authors.lastname: Rahimpour
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
authors.forename: Barbara
authors.initials: B
authors.lastname: Ikejiri
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D000107:Acetylation; D060746:Endoplasmic Reticulum-Associated Degradation; D005776:Gaucher Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D018841:HSP90 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D056572:Histone Deacetylase Inhibitors; D018832:Molecular Chaperones; D050505:Mutant Proteins; D011994:Recombinant Proteins; D005962:Glucosylceramidase