Misfolding of Lysosomal α-Galactosidase a in a Fly Model and its Alleviation by the Pharmacological Chaperone Migalastat
| Autor: | Gali Maor, Maria Papazian, Jan Lukas, Arndt Rolfs, Mia Horowitz, Hila Braunstein |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
UPR 3
Protein Folding genetic structures Fluorescent Antibody Technique Endoplasmic Reticulum misfolding 2 lcsh:Chemistry Animals Genetically Modified chemistry.chemical_compound Migalastat ERAD 4 migalastat 5 lcsh:QH301-705.5 Spectroscopy Fabry disease 1 biology Cell Death Chemistry Brain ER retention General Medicine Endoplasmic Reticulum-Associated Degradation Computer Science Applications Cell biology Pharmacological chaperone Drosophila melanogaster lipids (amino acids peptides and proteins) hormones hormone substitutes and hormone antagonists medicine.drug 1-Deoxynojirimycin Cell Survival Globotriaosylceramide Endoplasmic-reticulum-associated protein degradation Catalysis Article Inorganic Chemistry medicine Animals cardiovascular diseases Physical and Theoretical Chemistry Molecular Biology Endoplasmic reticulum Dopaminergic Neurons Organic Chemistry nutritional and metabolic diseases lcsh:Biology (General) lcsh:QD1-999 Chaperone (protein) alpha-Galactosidase biology.protein Unfolded protein response Unfolded Protein Response Fabry Disease Lysosomes |
| Zdroj: | International Journal of Molecular Sciences Volume 21 Issue 19 International Journal of Molecular Sciences, Vol 21, Iss 7397, p 7397 (2020) |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms21197397 |
| Popis: | Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal &alpha galactosidase A (&alpha Gal A). Due to these mutations, there is accumulation of globotriaosylceramide (GL-3) in plasma and in a wide range of cells throughout the body. Like other lysosomal enzymes, &alpha Gal A is synthesized on endoplasmic reticulum (ER) bound polyribosomes, and upon entry into the ER it undergoes glycosylation and folding. It was previously suggested that &alpha Gal A variants are recognized as misfolded in the ER and undergo ER-associated degradation (ERAD). In the present study, we used Drosophila melanogaster to model misfolding of &alpha Gal A mutants. We did so by creating transgenic flies expressing mutant &alpha Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known &alpha Gal A chaperone, migalastat. Our results showed that the A156V and the A285D &alpha Gal A mutants underwent ER retention, which led to activation of unfolded protein response (UPR) and ERAD. UPR could be alleviated by migalastat. When expressed in the fly&rsquo s dopaminergic cells, misfolding of &alpha Gal A and UPR activation led to death of these cells and to a shorter life span, which could be improved, in a mutation-dependent manner, by migalastat. |
| Databáze: | OpenAIRE |
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