Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Sawkar, Anu R.; Cheng, Wei‐Chieh; Beutler, Ernest; Wong, Chi‐Huey; Balch, William E.; Kelly, Jeffery W.

doi:10.1073/pnas.192582899

Cited by 484 publications

(481 citation statements)

References 33 publications

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“…While both treatments are effective in improving the hematologic and visceral symptoms in patients with mild, non-neuronopathic forms of the disease, their efficacy may be limited by their inability to cross the blood-brain barrier (ERT) or adverse side effects (SRT). Recent studies have demonstrated the ability of sugar analog inhibitors to increase the activity of mutant lysosomal enzymes in patient fibroblasts by acting as pharmacological chaperones [10][11][12][13][14][15]. As active site inhibitors, these compounds bind to the mutant enzymes and stabilize them in the ER, thereby preventing their ER-associated degradation and facilitating their folding and transport out of this compartment to lysosomes.…”

Section: Discussionmentioning

confidence: 99%

“…Since fibroblasts derived from different N370S/N370S Gaucher patients can exhibit variable GlcCerase residual activity [2,10,15], we tested the ability of IFG to enhance enzyme activity from multiple N370S patient fibroblasts. The results are summarized in Table I.…”

Section: Ifg Enhances the Activity Of N370s Glccerasementioning

confidence: 99%

“…Several researchers have demonstrated the ability of iminosugars to increase the activity of mutant forms of GlcCerase [10][11][12][13][14][15]. We have recently reported that the iminosugar, isofagomine (IFG), enhances N370S GlcCerase activity by approximately 3-fold by facilitating its folding and transport out of the ER to lysosomes.…”

Section: Introductionmentioning

confidence: 99%

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Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Steet

Chung

Lee

et al. 2007

Biochemical Pharmacology

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Gaucher disease is a lysosomal glycolipid storage disorder characterized by defects in acid-β-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. We recently demonstrated that isofagomine (IFG), an iminosugar that binds to the active site of GlcCerase, enhances the folding, transport and activity of the N370S mutant form of GlcCerase. In this study we compared the effects of IFG on a number of other glucosidases and glucosyltransferases. We report that IFG has little or no inhibitory activity towards intestinal disaccharidase enzymes, ER α-glucosidase II or glucosylceramide synthase at concentrations previously shown to enhance N370S GlcCerase folding and trafficking in Gaucher fibroblasts. Furthermore, treatment of wild type fibroblasts with high doses of IFG did not alter the processing of newly synthesized N-linked oligosaccharides. These findings support further evaluation of IFG as a potential therapeutic agent in the treatment of some forms of Gaucher disease.

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Section: Discussionmentioning

confidence: 99%

Section: Ifg Enhances the Activity Of N370s Glccerasementioning

confidence: 99%

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Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Steet

Chung

Lee

et al. 2007

Biochemical Pharmacology

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“…[7] Two GD patient fibroblast cell lines, one harboring N370S/N370S and the other F213I/L444P GCase mutations, were treated with IFG for five days and intracellular GCase activity following lysis of cells was determined with the aid of the artificial substrate 4-methylum-belliferylbeta-D-glucopyranoside (MUGlc). [30,31] An increase in enzymatic activity is observed as an increase in fluorescence upon release of the 4-methylumbelliferyl fluorophore. Treatment of N370S/N370S and F213I/L444P fibroblasts with 25 μM IFG for five days enhanced GCase activity 2.5-and 4.3-fold over non-pretreated cells, respectively (see Figure 1C).…”

Section: Ifg Enhances Global Stability and Activitymentioning

confidence: 99%

Isofagomine Induced Stabilization of Glucocerebrosidase

Kornhaber¹,

Tropak

Maegawa

et al. 2008

ChemBioChem

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Structurally destabilizing mutations in acid β-glucosidase (GCase) can result in Gaucher disease (GD). The iminosugar isofagomine (IFG), a competitive inhibitor and a potential pharmacological chaperone of GCase, is currently undergoing clinical evaluation for the treatment of GD. An X-ray crystallographic study of the GCase-IFG complex revealed a hydrogen bonding network between IFG and certain active site residues. It was suggested that this network may translate into greater global stability. Here it is demonstrated that IFG does increase the global stability of wild-type GCase, shifting its melting curve by ~15 °C and that it enhances mutant GCase activity in pretreated N370S/N370S and F213I/L444P patient fibroblasts. Additionally, amide hydrogen/ deuterium exchange mass spectroscopy (H/D-Ex) was employed to identify regions within GCase that undergo stabilization upon IFG-binding. H/D-Ex data indicate that the binding of IFG not only restricts the local protein dynamics of the active site, but also propagates this effect into surrounding regions.

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“…To this end, small molecular chaperones designed to cross the blood–brain barrier that are capable of increasing GCase activity are being investigated as a novel therapy for PD to decrease α‐synuclein levels 17, 18, 19, 20, 21, 22, 23, 24, 25…”

mentioning

confidence: 99%

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

Migdalska‐Richards

Daly

Bézard

et al. 2016

Annals of Neurology

159

138

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ObjectiveGaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α‐synuclein and phosphorylated α‐synuclein protein levels in mice.MethodsMice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α‐synuclein and phosphorylated α‐synuclein protein levels.ResultsAmbroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild‐type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α‐synuclein. Furthermore, in the mice overexpressing human α‐synuclein, ambroxol treatment decreased both α‐synuclein and phosphorylated α‐synuclein protein levels.InterpretationOur work supports the proposition that ambroxol should be further investigated as a potential novel disease‐modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α‐synuclein and phosphorylated α‐synuclein protein levels. Ann Neurol 2016;80:766–775

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Chemical chaperones increase the cellular activity of N370S β-glucosidase: A therapeutic strategy for Gaucher disease

Cited by 484 publications

References 33 publications

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Selective action of the iminosugar isofagomine, a pharmacological chaperone for mutant forms of acid-β-glucosidase

Isofagomine Induced Stabilization of Glucocerebrosidase

Ambroxol effects in glucocerebrosidase and α‐synuclein transgenic mice

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