2009
DOI: 10.1002/humu.21121
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The pharmacological chaperone 1-deoxynojirimycin increases the activity and lysosomal trafficking of multiple mutant forms of acid alpha-glucosidase

Abstract: Pompe disease is a lysosomal storage disorder (LSD) caused by mutations in the gene that encodes acid alpha-glucosidase (GAA). Recently, small molecule pharmacological chaperones have been shown to increase protein stability and cellular levels for mutant lysosomal enzymes and have emerged as a new therapeutic strategy for the treatment of LSDs. In this study, we characterized the pharmacological chaperone 1-deoxynojirimycin (DNJ) on 76 different mutant forms of GAA identified in Pompe disease. DNJ significant… Show more

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Cited by 82 publications
(101 citation statements)
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“…This therapy is based on the concept that imino sugars including DNJ and NB-DNJ interact with mutant GAA proteins, and thereby improve their stability and transportation to lysosomes. 13,14,28 However, these imino sugars are potent inhibitors of a-glucosidases including GAA and intestinal maltase-glucoamylase, and the administration of an excess dose results in intracellular storage of glycogen, 29 and glucosylated and galactosylated oligosaccharides. 30 So, it seems to be difficult to determine the proper doses of these chemicals for pharmacological chaperone therapy, and inadequate doses of them would worsen Pompe disease and might lead to diarrhea.…”
Section: Discussionmentioning
confidence: 99%
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“…This therapy is based on the concept that imino sugars including DNJ and NB-DNJ interact with mutant GAA proteins, and thereby improve their stability and transportation to lysosomes. 13,14,28 However, these imino sugars are potent inhibitors of a-glucosidases including GAA and intestinal maltase-glucoamylase, and the administration of an excess dose results in intracellular storage of glycogen, 29 and glucosylated and galactosylated oligosaccharides. 30 So, it seems to be difficult to determine the proper doses of these chemicals for pharmacological chaperone therapy, and inadequate doses of them would worsen Pompe disease and might lead to diarrhea.…”
Section: Discussionmentioning
confidence: 99%
“…Furthermore, the mutant GAA species for which imino sugars are effective are limited. 13,14,28 Hence, characterization of mutant GAAs responsive to imino sugars, and detailed information about the complex formation of a mutant GAA and an imino sugar are strongly required for improvement of pharmacological chaperone therapy.…”
Section: Discussionmentioning
confidence: 99%
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“…On the other hand, chaperone therapy appears to be feasible only in patients with responsive mutations mostly located in specific domains of the enzymatic protein (36).…”
Section: Small Molecule Pharmacological Chaperonesmentioning
confidence: 99%
“…Various inhibitors derived from deoxynojirimycin (DNJ) have been evaluated as pharmacological chaperones, in different lysosomal storage disorders (62). 1-deoxynojirimycin (DNJ) and N-butyl-DNJ (NBJ) were investigated in fibroblasts from Pompe patients (63,64). A significant increase of GAA activity was observed in fibroblasts from patients carrying different GAA mutants such as L552P, G549R, Y445F, and P545L mutations.…”
Section: Pharmacological Chaperonesmentioning
confidence: 99%