title: Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase.
abstract: Gaucher disease (GD) is characterized by accumulation of glucosylceramide in lysosomes due to mutations in the GBA1 gene encoding the lysosomal hydrolase β-glucocerebrosidase (GCase). The disease has a broad spectrum of phenotypes, which were divided into three different Types; Type 1 GD is not associated with primary neurological disease while Types 2 and 3 are associated with central nervous system disease. GCase molecules are synthesized on endoplasmic reticulum (ER)-bound polyribosomes, translocated into the ER and following modifications and correct folding, shuttle to the lysosomes. Mutant GCase molecules, which fail to fold correctly, undergo ER associated degradation (ERAD) in the proteasomes, the degree of which is one of the factors that determine GD severity. Several pharmacological chaperones have already been shown to assist correct folding of mutant GCase molecules in the ER, thus facilitating their trafficking to the lysosomes. Ambroxol, a known expectorant, is one such chaperone. Here we show that ambroxol increases both the lysosomal fraction and the enzymatic activity of several mutant GCase variants in skin fibroblasts derived from Type 1 and Type 2 GD patients.
authors.affiliation: Department of Cell Research and Immunology, Tel Aviv University, Ramat Aviv, Israel.
authors.forename: Inna
authors.initials: I
authors.lastname: Bendikov-Bar
authors.forename: Gali
authors.initials: G
authors.lastname: Maor
authors.forename: Mirella
authors.initials: M
authors.lastname: Filocamo
authors.forename: Mia
authors.initials: M
authors.lastname: Horowitz
mesh_terms: D000551:Ambroxol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004721:Endoplasmic Reticulum / Q000502:physiology; D056947:Enzyme Replacement Therapy; D004795:Enzyme Stability / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D005776:Gaucher Disease / Q000188:drug therapy* / Q000473:pathology; D005962:Glucosylceramidase / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology; D056687:Off-Label Use; D061251:Primary Cell Culture; D017510:Protein Folding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012867:Skin
chemical_list: D000551:Ambroxol; D005962:Glucosylceramidase