title: Histone deacetylase inhibitors prevent the degradation and restore the activity of glucocerebrosidase in Gaucher disease.
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.
authors.affiliation: Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892-1414, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Lu
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Masako
authors.initials: M
authors.lastname: Chen
authors.forename: Donald Y
authors.initials: DY
authors.lastname: Ye
authors.forename: Russell R
authors.initials: RR
authors.lastname: Lonser
authors.forename: Roscoe O
authors.initials: RO
authors.lastname: Brady
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
mesh_terms: D015153:Blotting, Western; D003001:Cloning, Molecular; D005347:Fibroblasts; D005776:Gaucher Disease / Q000188:drug therapy / Q000235:genetics*; D005962:Glucosylceramidase / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding; D055550:Protein Stability / Q000187:drug effects*; D059748:Proteolysis / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D018840:HSP70 Heat-Shock Proteins; D056572:Histone Deacetylase Inhibitors; D005962:Glucosylceramidase