Abstract
Gaucher's disease (GD) is characterized by loss of lysosomal glucocerebrosidase (GC) activity. Mutations in the gene encoding GC destabilize the protein's native folding leading to ER-associated degradation (ERAD) of the misfolded enzyme. Enhancing the cellular folding capacity by remodeling the proteostasis network promotes native folding and lysosomal activity of mutated GC variants. However, proteostasis modulators reported so far, including ERAD inhibitors, trigger cellular stress and lead to induction of apoptosis. We show herein that lacidipine, an L-type Ca(2+) channel blocker that also inhibits ryanodine receptors on the ER membrane, enhances folding, trafficking and lysosomal activity of the most severely destabilized GC variant achieved via ERAD inhibition in fibroblasts derived from patients with GD. Interestingly, reprogramming the proteostasis network by combining modulation of Ca(2+) homeostasis and ERAD inhibition remodels the unfolded protein response and dramatically lowers apoptosis induction typically associated with ERAD inhibition.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Calcium / metabolism
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Cell Death / drug effects
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Cytoprotection / drug effects
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Cytosol / drug effects
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Cytosol / metabolism
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Dihydropyridines / pharmacology
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum Chaperone BiP
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Endoplasmic Reticulum-Associated Degradation* / drug effects
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Fibroblasts / pathology
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Gaucher Disease / enzymology
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Gaucher Disease / pathology
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Gene Silencing / drug effects
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Glucosylceramidase / genetics*
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Glucosylceramidase / metabolism
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Heat-Shock Proteins / metabolism
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Homeostasis / drug effects
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Humans
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Lysosomes / drug effects
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Lysosomes / metabolism
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Mutant Proteins / metabolism
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Mutation / genetics*
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Protein Folding* / drug effects
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Protein Transport / drug effects
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Unfolded Protein Response / drug effects
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Up-Regulation / drug effects
Substances
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Dihydropyridines
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Endoplasmic Reticulum Chaperone BiP
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Heat-Shock Proteins
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Mutant Proteins
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Proto-Oncogene Proteins c-bcl-2
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lacidipine
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Glucosylceramidase
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Calcium
Grants and funding
This work was supported by the Virginia and L.E. Simmons Family Foundation and by the Sid W. Richardson Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.