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Article

Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat

1
The Shmunis School of Biomedicine and Cancer Research, Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel
2
Department of Neurology, Translational Neurodegeneration Section “Albrecht-Kossel“, University Medical Center Rostock, Rostock 18051, Germany
3
Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18051 Rostock, Germany
4
Centogene AG, 18055 Rostock, Germany
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(19), 7397; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197397
Received: 15 July 2020 / Revised: 4 October 2020 / Accepted: 5 October 2020 / Published: 7 October 2020
(This article belongs to the Special Issue Endoplasmic Reticulum Stress and Unfolded Protein Response 2.0)
Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal α-galactosidase A (α-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, α-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 α-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 α-Gal A mutants. We did so by creating transgenic flies expressing mutant α-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known α-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D α-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’s dopaminergic cells, misfolding of α-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. View Full-Text
Keywords: Fabry disease 1; misfolding 2; UPR 3; ERAD 4; migalastat 5 Fabry disease 1; misfolding 2; UPR 3; ERAD 4; migalastat 5
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MDPI and ACS Style

Braunstein, H.; Papazian, M.; Maor, G.; Lukas, J.; Rolfs, A.; Horowitz, M. Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat. Int. J. Mol. Sci. 2020, 21, 7397. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197397

AMA Style

Braunstein H, Papazian M, Maor G, Lukas J, Rolfs A, Horowitz M. Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat. International Journal of Molecular Sciences. 2020; 21(19):7397. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197397

Chicago/Turabian Style

Braunstein, Hila, Maria Papazian, Gali Maor, Jan Lukas, Arndt Rolfs, and Mia Horowitz. 2020. "Misfolding of Lysosomal α-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat" International Journal of Molecular Sciences 21, no. 19: 7397. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197397

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