{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T16:21:10Z","timestamp":1779121270693,"version":"3.51.4"},"reference-count":31,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T00:00:00Z","timestamp":1474070400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000025","name":"National Institute of Mental Health","doi-asserted-by":"crossref","award":["5R03MH098689-02"],"award-info":[{"award-number":["5R03MH098689-02"]}],"id":[{"id":"10.13039\/100000025","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health.","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Neuroscience Research"],"published-print":{"date-parts":[[2016,11]]},"abstract":"<jats:p>Krabbe's disease, also known as <jats:italic>globoid cell leukodystrophy<\/jats:italic> (GLD), is a lysosomal storage disease caused by the deficiency of the lysosomal enzyme \u03b2\u2010galactocerebrosidase (GALC), resulting in severe neurological manifestations related to demyelination secondary to elevated galactosylsphingosine (psychosine) with its subsequent cytotoxicity. The only available treatment is hematopoietic stem cell transplantation, which delays disease onset but does not prevent long\u2010term neurological manifestations. This article describes the identification of small molecules that enhance mutant GALC activity, identified by quantitative cell\u2010based high\u2010throughput screening (qHTS). Using a specific neurologically relevant murine cell line (145M\u2010<jats:italic>Twi<\/jats:italic>) modified to express common human h<jats:italic>GALC<\/jats:italic>\u2010G270D mutant, we were able to detect GALC activity in a 1,536\u2010well microplate format. The qHTS of approximately 46,000 compounds identified three small molecules that showed significant enhancements of residual mutant GALC activity in primary cell lines from GLD patients. These compounds were shown to increase the levels of GALC\u2010G270D mutant in the lysosomal compartment. In kinetic assessments, these small molecules failed to disturb the GALC kinetic profile under acidic conditions, which is highly desirable for folding\u2010assisting molecules operating in the endoplasmic reticulum and not affecting GALC catalytic properties in the lysosomal compartment. In addition, these small molecules rescued the decreased GALC activity at neutral pH and partially stabilized GALC under heat\u2010denaturating conditions. These drug\u2010like compounds can be used as the starting point to develop novel small\u2010molecule agents to treat the progressive neurodegenerative course of GLD. \u00a9 2016 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/jnr.23875","type":"journal-article","created":{"date-parts":[[2016,9,17]],"date-time":"2016-09-17T11:22:31Z","timestamp":1474111351000},"page":"1231-1245","source":"Crossref","is-referenced-by-count":2,"title":["Cell\u2010based high\u2010throughput screening identifies galactocerebrosidase enhancers as potential small\u2010molecule therapies for <scp>K<\/scp>rabbe's disease"],"prefix":"10.1002","volume":"94","author":[{"given":"Dae Song","family":"Jang","sequence":"first","affiliation":[{"name":"Department of Pediatrics University of Florida Gainesville Florida"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenjuan","family":"Ye","sequence":"additional","affiliation":[{"name":"National Institutes of Health Center for Advancing Translational 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