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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2013

Open Access 01-12-2013 | Research

Unfolded protein response in Gaucher disease: from human to Drosophila

Authors: Gali Maor, Sigal Rencus-Lazar, Mirella Filocamo, Hermann Steller, Daniel Segal, Mia Horowitz

Published in: Orphanet Journal of Rare Diseases | Issue 1/2013

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Abstract

Background

In Gaucher disease (GD), resulting from mutations in the GBA gene, mutant β-glucocerebrosidase (GCase) molecules are recognized as misfolded in the endoplasmic reticulum (ER). They are retrotranslocated to the cytoplasm, where they are ubiquitinated and undergo proteasomal degradation in a process known as the ER Associated Degradation (ERAD). We have shown in the past that the degree of ERAD of mutant GCase correlates with GD severity.
Persistent presence of mutant, misfolded protein molecules in the ER leads to ER stress and evokes the unfolded protein response (UPR).

Methods

We investigated the presence of UPR in several GD models, using molecular and behavioral assays.

Results

Our results show the existence of UPR in skin fibroblasts from GD patients and carriers of GD mutations. We could recapitulate UPR in two different Drosophila models for carriers of GD mutations: flies heterozygous for the endogenous mutant GBA orthologs and flies expressing the human N370S or L444P mutant GCase variants. We encountered early death in both fly models, indicating the deleterious effect of mutant GCase during development. The double heterozygous flies, and the transgenic flies, expressing mutant GCase in dopaminergic/serotonergic cells developed locomotion deficit.

Conclusion

Our results strongly suggest that mutant GCase induces the UPR in GD patients as well as in carriers of GD mutations and leads to development of locomotion deficit in flies heterozygous for GD mutations.
Appendix
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Metadata
Title
Unfolded protein response in Gaucher disease: from human to Drosophila
Authors
Gali Maor
Sigal Rencus-Lazar
Mirella Filocamo
Hermann Steller
Daniel Segal
Mia Horowitz
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2013
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/1750-1172-8-140

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