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Previous studies indicate blood\u2013brain barrier (BBB) defects in JNCL, and our earlier report showed prominent<jats:italic>Cln3<\/jats:italic>expression in mouse brain endothelium. Here we find that CLN3 is necessary for normal trafficking of the microdomain-associated proteins caveolin-1, syntaxin-6, and multidrug resistance protein 1 (MDR1) in brain endothelial cells. Correspondingly, CLN3-null cells have reduced caveolae, and impaired caveolae- and MDR1-related functions including endocytosis, drug efflux, and cell volume regulation. We also detected an abnormal blood\u2013brain barrier response to osmotic stress<jats:italic>in vivo<\/jats:italic>. Evaluation of the plasma membrane with fluorescent sphingolipid probes suggests microdomain destabilization and enhanced fluidity in CLN3-null cells. In further work we found that application of the glycosphingolipid lactosylceramide to CLN3-deficient cells rescues protein transport and caveolar endocytosis. Last, we show that CLN3 localizes to the trans-Golgi network (TGN) and partitions with buoyant microdomain fractions. We propose that CLN3 facilitates TGN-to-plasma membrane transport of microdomain-associated proteins. Insult to this pathway may underlie BBB dysfunction and contribute to JNCL pathogenesis.<\/jats:p>","DOI":"10.1523\/jneurosci.0498-13.2013","type":"journal-article","created":{"date-parts":[[2013,11,13]],"date-time":"2013-11-13T17:43:11Z","timestamp":1384364591000},"page":"18065-18079","source":"Crossref","is-referenced-by-count":61,"title":["CLN3 Loss Disturbs Membrane Microdomain Properties and Protein Transport in Brain Endothelial Cells"],"prefix":"10.1523","volume":"33","author":[{"given":"Luis","family":"Tecedor","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen S.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark 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