Gaucher Disease

Edmunds, Tim

doi:10.1002/9780470572702.ch21

Cited by 3 publications

(3 citation statements)

References 67 publications

(78 reference statements)

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“…In fact, the extent of the folding, trafficking and lysosomal activity enhancement appears to be dependent on the stability of the mutant GCase–the more unstable the GCase variant, the greater the activity enhancement observed. The L444P GCase variant is more destabilized at pH 7 in the ER compared to the N370S GCase mutant (Edmunds, 2010; Sawkar, et al, 2006; Schmitz, et al, 2005), and hence is degraded more extensively by ERAD (Ron and Horowitz, 2005). WT GCase is processed normally in the ER (Bendikov-Bar and Horowitz, 2012; Ron and Horowitz, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…The most common LSD is Gaucher’s disease (GD), which is characterized by the accumulation of the β-glucocerebrosidase (GCase; encoded by the GBA gene) substrates, glucosylceramide and glucosylsphingosine (Edmunds, 2010; Hruska, et al, 2008). Distinct GCase mutations are subject to varying degrees of ERAD and thus exhibit different levels of residual lysosomal GCase activity–generally, the lower the activity, the more severe the GD phenotype (Bendikov-Bar and Horowitz, 2012; Grace, et al, 1994; Ron and Horowitz, 2005; Schmitz, et al, 2005; Schueler, et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…L444P homozygotes exhibiting extremely low levels of lysosomal GCase activity present with neuronopathic GD (Grabowski, 1997; Schmitz, et al, 2005). N370S GCase, exhibiting higher residual lysosomal activity, never presents with any central nervous system symptoms, even in compound heterozygotes with one null allele (Edmunds, 2010). Instead these patients present with hepatosplenomegaly and skeletal disorders, clinical features common to most GD patients (Beutler and Gelbart, 1993; Tsuji, et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

Tan

Genereux

Pankow

et al. 2014

Chemistry & Biology

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SUMMARY Gaucher’s disease (GD) is caused by mutations that compromise β-glucocerebrosidase (GCase) folding in the endoplasmic reticulum (ER), leading to excessive degradation instead of trafficking, which results in insufficient lysosomal function. We hypothesized that ER GCase interacting proteins play critical roles in making quality control decisions, i.e., facilitating ER-associated degradation (ERAD) instead of folding and trafficking. Utilizing GCase immunoprecipitation followed by mass spectrometry-based proteomics, we identified endogenous HeLa cell GCase protein interactors, including ERdj3, an ER resident Hsp40 not previously established to interact with GCase. Depleting ERdj3 reduced the rate of mutant GCase degradation in patient-derived fibroblasts, while increasing folding, trafficking and function by directing GCase to the pro-folding ER calnexin pathway. Inhibiting ERdj3-mediated mutant GCase degradation while simultaneously enhancing calnexin-associated folding, by way of a diltiazem-mediated increase in ER Ca2+ levels, yields a synergistic rescue of L444P GCase lysosomal function. Our findings suggest a combination therapeutic strategy for ameliorating GD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

Tan

Genereux

Pankow

et al. 2014

Chemistry & Biology

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Chemical Probes of Sphingolipid Metabolizing Enzymes

Nieves

Sanllehí

Abad

et al. 2015

Bioactive Sphingolipids in Cancer Biology and Therapy

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Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators

Muntau

Leandro

Staudigl

et al. 2014

J of Inher Metab Disea

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To attain functionality, proteins must fold into their three-dimensional native state. The intracellular balance between protein synthesis, folding, and degradation is constantly challenged by genetic or environmental stress factors. In the last ten years, protein misfolding induced by missense mutations was demonstrated to be the seminal molecular mechanism in a constantly growing number of inborn errors of metabolism. In these cases, loss of protein function results from early degradation of missense-induced misfolded proteins. Increasing knowledge on the proteostasis network and the protein quality control system with distinct mechanisms in different compartments of the cell paved the way for the development of new treatment strategies for conformational diseases using small molecules. These comprise proteostasis regulators that enhance the capacity of the proteostasis network and pharmacological chaperones that specifically bind and rescue misfolded proteins by conformational stabilization. They can be used either alone or in combination, the latter to exploit synergistic effects. Many of these small molecule compounds currently undergo preclinical and clinical pharmaceutical development and two have been approved: saproterin dihydrochloride for the treatment of phenylketonuria and tafamidis for the treatment of transthyretin-related hereditary amyloidosis. Different technologies are exploited for the discovery of new small molecule compounds that belong to the still young class of pharmaceutical products discussed here. These compounds may in the near future improve existing treatment strategies or even offer a first-time treatment to patients suffering from nowadays-untreatable inborn errors of metabolism.

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Gaucher Disease

Cited by 3 publications

References 67 publications

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

ERdj3 Is an Endoplasmic Reticulum Degradation Factor for Mutant Glucocerebrosidase Variants Linked to Gaucher’s Disease

Chemical Probes of Sphingolipid Metabolizing Enzymes

Innovative strategies to treat protein misfolding in inborn errors of metabolism: pharmacological chaperones and proteostasis regulators

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