Unfolded protein response in Gaucher disease: from human to Drosophila

Orphanet Journal of Rare Diseases

Mia Horowitz⁴  Daniel Segal¹  Hermann Steller³  Mirella Filocamo²  Sigal Rencus-Lazar⁴  Gali Maor⁴ 

[1] Sagol Interdisciplinary School of Neurosciences, Tel Aviv University, Tel Aviv 69978, Israel;Centro di Diagnostica Genetica e Biochimica delle Malattie Metaboliche, IRCCS G. Gaslini Genoa, Italy;Howard Hughes Medical Institute, Strang Laboratory of Cancer Research, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA;Department of Cell Research and Immunology, Tel Aviv University, Levanon St, Ramat Aviv 69978, Israel

关键词: UPR;    ERAD;    Glucocerebrosidase;    Parkinson’s disease;    Gaucher disease;   

Others  :  863559
DOI  :  10.1186/1750-1172-8-140

 received in 2013-06-05, accepted in 2013-08-19,  发布年份 2013

【 摘 要 】

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.

【 授权许可】

   
2013 Maor et al.; licensee BioMed Central Ltd.

【 图 表 】

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