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

Yam, Gary Hin‐Fai; Bosshard, Nils U.; Zuber, Christian; Steinmann, Beat; Roth, Jürgen

doi:10.1152/ajpcell.00426.2005

Cited by 115 publications

(94 citation statements)

References 38 publications

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“…Several groups have shown that 1-deoxygalactonojirimycin corrects the trafficking defect in six mutants of ␣-galactosidase A, the enzyme that is deficient in Fabry disease (17,18,30). This pharmacological chaperone binds to the active site of the enzyme at the neutral pH of the ER to assist folding and enhance transport out of this organelle, but it dissociates in the low-pH environment of the lysosome.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of several glucose and galactose analogs to increase the activity of the defective enzymes in Gaucher and Fabry disease cells, respectively, has been recently demonstrated by several groups (15)(16)(17)(18)(19)(20). Although the increased enzyme activity is believed to result from improved folding and trafficking of the mutant enzymes, insight into the actual mechanisms whereby these small molecules exert their action is limited.…”

mentioning

confidence: 99%

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The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Steet

Chung

Wustman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

203

233

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Gaucher disease is a lysosomal storage disorder caused by deficiency in lysosomal acid ␤-glucosidase (GlcCerase), the enzyme responsible for the catabolism of glucosylceramide. One of the most prevalent disease-causing mutations, N370S, results in an enzyme with lower catalytic activity and impaired exit from the endoplasmic reticulum. Here, we report that the iminosugar isofagomine (IFG), an active-site inhibitor, increases GlcCerase activity 3.0 ؎ 0.6-fold in N370S fibroblasts by several mechanisms. A major effect of IFG is to facilitate the folding and transport of newly synthesized GlcCerase in the endoplasmic reticulum, thereby increasing the lysosomal pool of the enzyme. In addition, N370S GlcCerase synthesized in the presence of IFG exhibits a shift in pH optimum from 6.4 to 5.2 and altered sensitivity to SDS. Although IFG fully inhibits GlcCerase in the lysosome in an in situ assay, washout of the drug leads to partial recovery of GlcCerase activity within 4 h and full recovery by 24 h. These findings provide support for the possible use of active-site inhibitors in the treatment of some forms of Gaucher disease.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

Steet

Chung

Wustman

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

203

233

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“…Previous studies have analyzed the subcellular site(s) of accumulation of misfolded proteins and shown that they may be stored throughout the ER (27) and may cause local dilatation or proliferation of the ER or induce proliferation of pre-Golgi intermediates (28)(29)(30)(31)(32)(33). However, the possible involvement of these induced structures in retrotranslocation of misfolded proteins remains enigmatic.…”

Section: Discussionmentioning

confidence: 99%

EDEM1 reveals a quality control vesicular transport pathway out of the endoplasmic reticulum not involving the COPII exit sites

Zuber

Cormier

Guhl

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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Immature and nonnative proteins are retained in the endoplasmic reticulum (ER) by the quality control machinery. Folding-incompetent glycoproteins are eventually targeted for ER-associated protein degradation (ERAD). EDEM1 (ER degradation-enhancing ␣-mannosidaselike protein 1), a putative mannose-binding protein, targets misfolded glycoproteins for ERAD. We report that endogenous EDEM1 exists mainly as a soluble glycoprotein. By high-resolution immunolabeling and serial section analysis, we find that endogenous EDEM1 is sequestered in buds that form along cisternae of the rough ER at regions outside of the transitional ER. They give rise to Ϸ150-nm vesicles scattered throughout the cytoplasm that are lacking a recognizable COPII coat. About 87% of the immunogold labeling was over the vesicles and Ϸ11% over the ER lumen. Some of the EDEM1 vesicles also contain Derlin-2 and the misfolded Hong Kong variant of ␣-1-antitrypsin, a substrate for EDEM1 and ERAD. Our results demonstrate the existence of a vesicle budding transport pathway out of the rough ER that does not involve the canonical transitional ER exit sites and therefore represents a previously unrecognized passageway to remove potentially harmful misfolded luminal glycoproteins from the ER.electron microscopy ͉ protein misfolding ͉ protein quality control T he folding state of newly synthesized glycoproteins in the endoplasmic reticulum (ER) is monitored by a quality control machinery (1). Increased formation of misfolded proteins disturbs ER homeostasis resulting in protein degradation, as well as cell damage and death. This is the cause of many human diseases including cystic fibrosis, ␣-1-antitrypsin deficiency, renal diabetes insipidus, and congenital goiter (2, 3).Orderly occurring processes can be distinguished during the life and death of a folding-incompetent glycoprotein. The first involves recognition by the quality control machinery (4-6). The lectin chaperones calnexin/calreticulin retain nonnative conformers with monoglucosylated glycans (5, 7). Mannose-trimmed glycans generated by ER-mannosidases appear to represent a quality control tag for routing misfolded glycoproteins to the ER-associated degradation (ERAD) (8-12). The current view is that misfolded, mannosetrimmed glycoproteins are then retrotranslocated to the cytoplasm, where they are ubiquitinated and deglycosylated before proteasomal degradation (13).EDEM1 (ER degradation-enhancing ␣-mannosidase-like protein 1) and its yeast ortholog Htm1p/Mnl1p are putative mannosebinding proteins (14-18) that are transcriptionally induced by ER stress (14,17,18). They are believed to target misfolded glycoproteins for proteasomal degradation by removing them from the calnexin/calreticulin cycle (14-17). The overexpression of EDEM1 results in the accelerated proteasomal degradation of ERAD substrates such as the Hong Kong variant of ␣-1-antitrypsin (HK A1AT) and a luminal variant of beta-secretase, whereas the deletion or knockdown of EDEM1/Htm1p reduces the degradation rates of the ERAD substrates ...

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“…Both in vivo and in vitro studies of these diseases have elucidated the role of particular chaperone compounds in decreasing misfolded protein aggregation, enhancing proper trafficking of the protein(s) in question to target sites, and ameliorating the overall disease phenotype. The success of chaperones in other disorders, such as nephrogenic diabetes insipidus and Parkinson's disease, is encouraging [21,31,32,38,50]. However, to date, no published studies have examined the use of chemical chaperones as a treatment for AMD in humans or in AMD models.…”

Section: Similarities Between Amd and Other Neurodegenerative Diseasementioning

confidence: 99%

“…The treatment of other neuronal and age-related diseases with chemical and pharmacological chaperones provides the foundation for research into their applications in AMD [38,50]. Although, there is no clear target for chaperone treatment in AMD, increasing the expression of native molecular chaperones would likely help the cells respond to the stressed environment of the aging AMD macula.…”

Section: Similarities Between Amd and Other Neurodegenerative Diseasementioning

confidence: 99%

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

Sauer

Patel

Chan

et al. 2008

Expert Review of Ophthalmology

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SUMMARYRecent studies suggest that pathological processes involved in age-related macular degeneration (AMD) might induce endoplasmic reticulum (ER) stress. Growing evidence demonstrates the ability of chemical chaperones to decrease ER stress and ameliorate ER stress-related disease phenotypes, suggesting that the field of chaperone therapy might hold novel treatments for AMD. In this review, we examine the evidence suggesting a role for ER stress in AMD. Furthermore, we discuss the use of chaperone therapy for the treatment of ER stress-associated diseases, including other neurodegenerative diseases and retinopathies. Finally, we examine strategies for identifying potential chaperone compounds and for experimentally demonstrating chaperone activity in in vitro and in vivo models of human disease.

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

Cited by 115 publications

References 38 publications

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

The iminosugar isofagomine increases the activity of N370S mutant acid β-glucosidase in Gaucher fibroblasts by several mechanisms

EDEM1 reveals a quality control vesicular transport pathway out of the endoplasmic reticulum not involving the COPII exit sites

Unfolding the therapeutic potential of chemical chaperones for age-related macular degeneration

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