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4-Phenylbutyrate rescues trafficking incompetent mutant alpha-galactosidase A without restoring its functionality |
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| Authors: | Yam Gary Hin-Fai Roth Jürgen Zuber Christian |
| Institution: | Division of Cell and Molecular Pathology, Department of Pathology, University of Zurich, CH-8091 Zürich, Switzerland. |
| Abstract: | Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A. Most mutant enzyme is catalytically active but due to misfolding retained in the endoplasmic reticulum. We have tested 4-phenylbutyrate for its potential to rescue various trafficking incompetent mutant alpha-galactosidase A. Although we found that the trafficking blockade for endoplasmic reticulum-retained mutant alpha-Gal A was released, neither a mature enzyme was detectable in transgenic mice fibroblasts nor a reversal of lysosomal Gb3 storage in fibroblasts from Fabry patients could be observed. Because of lack of functionality of rescued mutant alpha-galactosidase A, 4-phenylbutyrate seems to be of limited use as a chemical chaperone for Fabry disease. |
| Keywords: | α-Gal A α-galactosidase A ER endoplasmic reticulum 4-PBA sodium 4-phenylbutyrate UPR unfolded protein response ERAD ER-associated protein degradation FBS fetal bovine serum DGJ 1-deoxygalactonojirimycin Gb3 globotriosylceramide LAMP1 lysosomal-associated membrane protein1 |
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