Journal article
CLN3 Loss Disturbs Membrane Microdomain Properties and Protein Transport in Brain Endothelial Cells
The Journal of neuroscience, Vol.33(46), pp.18065-18079
11/13/2013
DOI: 10.1523/JNEUROSCI.0498-13.2013
PMCID: PMC3828460
PMID: 24227717
Abstract
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a fatal childhood-onset neurodegenerative disorder caused by mutations in ceroid lipofuscinosis neuronal-3 (CLN3), a hydrophobic transmembrane protein of unresolved function. Previous studies indicate blood-brain barrier (BBB) defects in JNCL, and our earlier report showed prominent Cln3 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-brain barrier response to osmotic stress in vivo. 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.
Details
- Title: Subtitle
- CLN3 Loss Disturbs Membrane Microdomain Properties and Protein Transport in Brain Endothelial Cells
- Creators
- Luis Tecedor - University of IowaColleen S. Stein - University of Iowa, Internal MedicineMark L. Schultz - Univ Iowa, Program Mol & Cell Biol, Iowa City, IA 52242 USAHany Farwanah - University of BonnKonrad Sandhoff - University of BonnBeverly L. Davidson - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.33(46), pp.18065-18079
- DOI
- 10.1523/JNEUROSCI.0498-13.2013
- PMID
- 24227717
- PMCID
- PMC3828460
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Soc Neuroscience
- Number of pages
- 15
- Grant note
- Roy J. Carver Trust R01NS034568 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS) Beyond Batten Foundation P30ES005605 / NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Environmental Health Sciences (NIEHS) DK 54759 / University of Iowa Central Microscopy Facility and Gene Transfer Vector Core Batten Disease Support and Research Association P30DK054759 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) NS 34568 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 11/13/2013
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Internal Medicine
- Record Identifier
- 9984366286302771
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