Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants.

@article{Yam2006PharmacologicalCC,
  title={Pharmacological chaperone corrects lysosomal storage in Fabry disease caused by trafficking-incompetent variants.},
  author={G.-F. Yam and Nils U. Bosshard and Christian Zuber and Beat Steinmann and J{\"u}rgen Roth},
  journal={American journal of physiology. Cell physiology},
  year={2006},
  volume={290 4},
  pages={
          C1076-82
        }
}
Fabry disease is a lysosomal storage disorder caused by deficiency of alpha-galactosidase A (alpha-Gal A) resulting in lysosomal accumulation of glycosphingolipid globotriosylceramide Gb3. Misfolded alpha-Gal A variants can have residual enzyme activity but are unstable. Their lysosomal trafficking is impaired because they are retained in the endoplasmic reticulum (ER) by quality control. Subinhibitory doses of the competitive inhibitor of alpha-Gal A, 1-deoxygalactonojirimycin (DGJ), stabilize… 
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Pharmacological chaperone therapy for Fabry disease
  • S. Ishii
  • Biology
    Proceedings of the Japan Academy. Series B, Physical and biological sciences
  • 2012
TLDR
It is discovered that a potent α-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells.
Review Pharmacological chaperone therapy for Fabry disease
TLDR
It is discovered that a potent ,-galactosidase A inhibitor, 1-deoxygalactonojirimycin, acts as a pharmacological chaperone to facilitate the proper folding of the mutant enzyme by binding to its active site, thereby improving its stability and trafficking to the lysosomes in mammalian cells.
Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat
TLDR
When expressed in the fly’s dopaminergic cells, misfolding of α-Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat.
α-Galactosidase Aggregation Is a Determinant of Pharmacological Chaperone Efficacy on Fabry Disease Mutants*
TLDR
The observations reinforce the idea that treatment of aggregation-associated loss of function observed for the more severe α-galactosidase mutants could be enhanced by combining pharmacological chaperone treatment with the suppression of mutant aggregation, e.g. via proteostatic regulator compounds that increase cellular chaper one expression.
The pharmacological chaperone 1-deoxygalactonojirimycin increases α-galactosidase A levels in Fabry patient cell lines
TLDR
The data indicate that DGJ merits further evaluation as a treatment for patients with Fabry disease with various missense mutations, and elevated GL-3 levels in responsive Fabry fibroblasts were reduced after DGJ incubation, indicating that increased mutant α-Gal A levels can reduce accumulated substrate.
Altered dynamics of a lipid raft associated protein in a kidney model of Fabry disease.
Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice
TLDR
Coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization, thus warranting clinical investigation.
Identification and characterization of pharmacological chaperones to correct enzyme deficiencies in lysosomal storage disorders.
TLDR
A wide range of in vitro assays are now available to measure mutant lysosomal enzyme interaction with and stabilization by PCs, as well as subsequent increases in cellular enzyme levels and function, which will be discussed in this review.
The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease.
TLDR
It is indicated that oral administration of DGJ increases mutant alpha-Gal A activity and reduces GL-3 in disease-relevant tissues in Tg/KO mice, and thus merits further evaluation as a treatment for Fabry disease.
Rescue of mutant alpha-galactosidase A in the endoplasmic reticulum by 1-deoxygalactonojirimycin leads to trafficking to lysosomes.
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