TY - JOUR
T1 - Ambroxol as a pharmacological chaperone for mutant glucocerebrosidase
AU - Bendikov-Bar, Inna
AU - Maor, Gali
AU - Filocamo, Mirella
AU - Horowitz, Mia
N1 - Funding Information:
We would like to thank Prof E Shprecher (Department of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel) for providing healthy skin fibroblasts and Prof EH Kolodny (NYU Medical Center, NY, USA) for the Gaucher patients cell lines. We also thank the “Cell Line and DNA Biobank from Patients Affected by Genetic Diseases” (G. Gaslini Institute), Telethon Genetic Biobank for GD skin fibroblasts. This work was supported by grants from the Israel Science Foundation and the Israeli Ministry of Health (to MH) and the Telethon Genetic Biobank Network Project No. GTB07001A (to MF).
PY - 2013/2
Y1 - 2013/2
N2 - 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.
AB - 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.
KW - Ambroxol
KW - ERAD
KW - Gaucher disease
KW - Glucocerebrosidase
UR - http://www.scopus.com/inward/record.url?scp=84871947340&partnerID=8YFLogxK
U2 - 10.1016/j.bcmd.2012.10.007
DO - 10.1016/j.bcmd.2012.10.007
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AN - SCOPUS:84871947340
SN - 1079-9796
VL - 50
SP - 141
EP - 145
JO - Blood Cells, Molecules, and Diseases
JF - Blood Cells, Molecules, and Diseases
IS - 2
ER -