{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,18]],"date-time":"2026-01-18T13:24:09Z","timestamp":1768742649029,"version":"3.49.0"},"reference-count":40,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2016,5,30]],"date-time":"2016-05-30T00:00:00Z","timestamp":1464566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Traffic"],"published-print":{"date-parts":[[2016,8]]},"abstract":"<jats:p>Krabbe disease is a severe, fatal neurodegenerative disorder caused by defects in the lysosomal enzyme galactocerebrosidase (<jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content>). The correct targeting of <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> to the lysosome is essential for the degradation of glycosphingolipids including the primary lipid component of myelin. Over 100 different mutations have been identified in <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> that cause Krabbe disease but the mechanisms by which they cause disease remain unclear. We have generated monoclonal antibodies against full\u2010length human <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> and used these to monitor the trafficking and processing of <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> variants in cell\u2010based assays and by immunofluorescence microscopy. Striking differences in the secretion, processing and endosomal targeting of <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> variants allows the classification of these into distinct categories. A subset of <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> variants are not secreted by cells, not proteolytically processed, and remain trapped in the <jats:styled-content style=\"fixed-case\">ER<\/jats:styled-content>; these are likely to cause disease due to protein misfolding and should be targeted for pharmacological chaperone therapies. Other <jats:styled-content style=\"fixed-case\">GALC<\/jats:styled-content> variants can be correctly secreted by cells and cause disease due to catalytic defects in the enzyme active site, inappropriate post\u2010translational modification or a potential inability to bind essential cofactors. The classification of disease pathogenesis presented here provides a molecular framework for appropriate targeting of future Krabbe disease therapies.<\/jats:p><jats:p><jats:inline-graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"graphic\/tra12404-gra-0001.png\" xlink:title=\"image\"\/><\/jats:p>","DOI":"10.1111\/tra.12404","type":"journal-article","created":{"date-parts":[[2016,4,30]],"date-time":"2016-04-30T15:17:57Z","timestamp":1462029477000},"page":"908-922","source":"Crossref","is-referenced-by-count":35,"title":["Molecular Mechanisms of Disease Pathogenesis Differ in Krabbe Disease Variants"],"prefix":"10.1111","volume":"17","author":[{"given":"Samantha J.","family":"Spratley","sequence":"first","affiliation":[{"name":"Cambridge Institute for Medical Research, Department of Pathology University of Cambridge  Cambridge CB2 0XY UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris 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