{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:01:33Z","timestamp":1787821293641,"version":"build-2784847793"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"23","license":[{"start":{"date-parts":[[2022,12,8]],"date-time":"2022-12-08T00:00:00Z","timestamp":1670457600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Niemann-Pick Canada","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Hope for Marian","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"University of Pennsylvania Orphan Disease Center","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Charles Woodson Collaborative Research Award","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"Support for Accelerated Research for Niemann-Pick Type C","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"NICHD","award":["ZIA HD008989"],"award-info":[{"award-number":["ZIA HD008989"]}]},{"name":"Ara Parseghian Medical Research Foundation","award":["none"],"award-info":[{"award-number":["none"]}]},{"name":"NIH Clinical Center Bench to Bedside Program","award":["none"],"award-info":[{"award-number":["none"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01 NS063967,R01 NS122746,K01 DK124450,R01NS114413"],"award-info":[{"award-number":["R01 NS063967,R01 NS122746,K01 DK124450,R01NS114413"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,12,8]]},"abstract":"<jats:p>\n                    The folding and trafficking of transmembrane glycoproteins are essential for cellular homeostasis and are compromised in many diseases. In Niemann-Pick type C disease, a lysosomal disorder characterized by impaired intracellular cholesterol trafficking, the transmembrane glycoprotein NPC1 misfolds due to disease-causing missense mutations. While mutant NPC1 has emerged as a robust target for proteostasis modulators, drug development efforts have been unsuccessful in mouse models. Here, we demonstrated unexpected differences in trafficking through the medial Golgi between mouse and human I1061T-NPC1, a common disease-causing mutant. We established that these distinctions are governed by differences in the NPC1 protein sequence rather than by variations in the endoplasmic reticulum\u2013folding environment. Moreover, we demonstrated direct effects of mutant protein trafficking on the response to small molecules that modulate the endoplasmic reticulum\u2013folding environment by affecting Ca\n                    <jats:sup>++<\/jats:sup>\n                    concentration. Finally, we developed a panel of isogenic human NPC1 iNeurons expressing WT, I1061T-, and R934L-NPC1 and demonstrated their utility in testing these candidate therapeutics. Our findings identify important rules governing mutant NPC1\u2019s response to proteostatic modulators and highlight the importance of species- and mutation-specific responses for therapy development.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.160308","type":"journal-article","created":{"date-parts":[[2022,10,27]],"date-time":"2022-10-27T12:00:56Z","timestamp":1666872056000},"source":"Crossref","is-referenced-by-count":15,"title":["Species-specific differences in NPC1 protein trafficking govern therapeutic response in Niemann-Pick type C disease"],"prefix":"10.1172","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3149-4424","authenticated-orcid":true,"given":"Mark L.","family":"Schultz","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan, 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