{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:12Z","timestamp":1787028432738,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T00:00:00Z","timestamp":1602028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014476","name":"Pfizer Pharmaceuticals","doi-asserted-by":"publisher","award":["000000"],"award-info":[{"award-number":["000000"]}],"id":[{"id":"10.13039\/100014476","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fabry disease, an X-linked recessive lysosomal disease, results from mutations in the GLA gene encoding lysosomal \u03b1-galactosidase A (\u03b1-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, \u03b1-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 \u03b1-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 \u03b1-Gal A mutants. We did so by creating transgenic flies expressing mutant \u03b1-Gal A variants and assessing development of ER stress, activation of the ER stress response and their relief with a known \u03b1-Gal A chaperone, migalastat. Our results showed that the A156V and the A285D \u03b1-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\u2019s dopaminergic cells, misfolding of \u03b1-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.<\/jats:p>","DOI":"10.3390\/ijms21197397","type":"journal-article","created":{"date-parts":[[2020,10,7]],"date-time":"2020-10-07T09:12:58Z","timestamp":1602061978000},"page":"7397","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Misfolding of Lysosomal \u03b1-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat"],"prefix":"10.3390","volume":"21","author":[{"given":"Hila","family":"Braunstein","sequence":"first","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Papazian","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gali","family":"Maor","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lukas","sequence":"additional","affiliation":[{"name":"Department of Neurology, Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201c, University Medical Center Rostock, Rostock 18051, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18051 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arndt","family":"Rolfs","sequence":"additional","affiliation":[{"name":"Centogene AG, 18055 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mia","family":"Horowitz","sequence":"additional","affiliation":[{"name":"The Shmunis School of Biomedicine and Cancer Research, Life Sciences, Tel Aviv University, Ramat Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1083\/jcb.201110131","article-title":"The impact of the unfolded protein response on human disease","volume":"197","author":"Wang","year":"2012","journal-title":"J. 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