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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
MeSH terms
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Acetylation
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Endoplasmic Reticulum-Associated Degradation
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Gaucher Disease / drug therapy*
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Gaucher Disease / enzymology*
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Gaucher Disease / genetics
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Gaucher Disease / metabolism
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Glucosylceramidase / genetics
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Glucosylceramidase / metabolism*
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HSP90 Heat-Shock Proteins / chemistry
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HSP90 Heat-Shock Proteins / genetics
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HSP90 Heat-Shock Proteins / metabolism
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Histone Deacetylase Inhibitors / pharmacology*
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Humans
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Models, Biological
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Molecular Chaperones / chemistry
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Molecular Chaperones / genetics
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Molecular Chaperones / metabolism*
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Mutagenesis, Site-Directed
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Mutation
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Protein Folding
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Recombinant Proteins / chemistry
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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HSP90 Heat-Shock Proteins
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HSP90AB1 protein, human
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Histone Deacetylase Inhibitors
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Molecular Chaperones
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Mutant Proteins
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Recombinant Proteins
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Glucosylceramidase