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Cln3p Impacts Galactosylceramide Transport, Raft Morphology, and Lipid Content

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Cln3p Impacts Galactosylceramide Transport, Raft Morphology, and Lipid Content 0031-3998/08/6306-0625 Vol. 63, No. 6, 2008 PEDIATRIC RESEARCH Printed in U.S.A. Copyright © 2008 International Pediatric Research Foundation, Inc. CLN3p Impacts Galactosylceramide Transport, Raft Morphology, and Lipid Content ELENA RUSYN, TALAL MOUSALLEM, DIXIE-ANN PERSAUD-SAWIN, SARA MILLER, AND ROSE-MARY N. BOUSTANY Departments of Neurobiology [E.R., T.M., D.-A.P.-S., R.-M.N.B.], Pathology [S.M.], Duke University Medical Center, Durham, North Carolina 27710; Abu-Haidar Neuroscience Institute [R.-M.N.B.], American University of Beirut, 11072020, Beirut, Lebanon ABSTRACT: Juvenile neuronal ceroid lipofuscinosis (JNCL) belongs CLN3p is highly conserved. Causes of cell death in the to the neuronal ceroid lipofuscinoses characterized by blindness/ brain/retina remain controversial. CLN3p imparts antiapop- seizures/motor/cognitive decline and early death. JNCL is caused by totic properties to neurons/cells (4) and regulates autophagy CLN3 gene mutations that negatively modulate cell growth/apoptosis. (5). CLN3-deficient cells have accelerated apoptosis and al- CLN3 protein (CLN3p) localizes to Golgi/Rab4-/Rab11-positive endo- tered ceramide/sphingomyelin levels that correct with the somes and lipid rafts, and harbors a galactosylceramide (GalCer) lipid raft-binding domain. Goals are proving CLN3p participates in GalCer addition of CLN3p. CLN3 mRNA/protein are overexpressed transport from Golgi to rafts, and GalCer deficits negatively affect cell in cancer cells (6). growth/apoptosis. GalCer/mutant CLN3p are retained in Golgi, with CLN3p is placed in HEK/HeLa endosomes (7), yeast vacu- CLN3p rescuing GalCer deficits in rafts. Diminishing GalCer in normal oles, mouse retinal cell mitochondria (8), neuronal synapto- cells by GalCer synthase siRNA negatively affects cell growth/ somes/synapses (9), nucleii of rat neurons (10), and Golgi/ apoptosis. GalCer restores JNCL cell growth. WT CLN3p binds GalCer, plasma membrane (PM) in HeLa/fibroblasts/COS-7 cells (11). but not mutant CLN3p. Sphingolipid content of rafts/Golgi is perturbed Wild-type (WT) CLN3p localizes to Golgi/PM and traffics via with diminished GalCer in rafts and accumulation in Golgi. CLN3- early recycling Rab4/Rab11-endosomes from Golgi to lipid deficient raft vesicular structures are small by transmission electron rafts (LR) in primary rat hippocampal neurons/postmitotic microscopy, reflecting altered sphingolipid composition of rafts. CLN1/ CLN2/CLN6 proteins bind to lysophosphatidic acid/sulfatide, CLN6/ human neurons and fibroblasts. Mutant CLN3p localizes to a CLN8 proteins to GalCer, and CLN8 protein to ceramide. Sphingolipid disrupted Golgi, fails to reach PM and mislocalizes to lyso- composition/morphology of CLN1-/CLN2-/CLN6-/CLN8- and CLN9- somes. CLN3p harbors a conserved motif, 291VYFAE295, deficient rafts are altered suggesting changes in raft structure/lipid necessary for cell growth/apoptosis embedded in a stretch of stoichiometry could be common themes underlying these diseases. amino acids structurally homologous to a GalCer lipid raft- (Pediatr Res 63: 625–631, 2008) binding domain. This domain defines a raft-binding site struc- turally identical in infectious prionic protein/␤-amyloid/V3 he Neuronal Ceroid Lipofuscinoses (NCL)/Batten disor- loop of the HIV-1 surface envelope glycoprotein, gp120 (12). Tders are pediatric diseases characterized by retinitis pig- Immunolabeling studies localize WT CLN3p with alkaline mentosa/seizures/mental and motor decline. The pathologic phosphatase/caveolin-1 to rafts and caveolae in some cells hallmark of NCL is neuronal loss. Pathophysiological theories (11). Mutant CLN3p minimally colocalizes to LRs. CLN3p include increased lipid peroxidation, altered dolichol turnover, rescues the PM GalCer deficit suggesting involvement in increased inflammation, subunit c of mitochondrial ATP syn- GalCer transport to PM/LRs. thase accumulation, and neuronal apoptosis (1). Rafts are involved in protein trafficking/protein-complex Juvenile neuronal ceroid lipofuscinosis (JNCL) is caused formation/signal transduction/apoptosis/cell adhesion/stress by CLN3 gene mutations (2). Most cases are due to a 1.02 responses/cytoskeleton regulation/conduction of proathero- kb genomic DNA deletion, resulting in truncated protein. genic stimuli, and affect immune function (13–15). Rafts are CLN3p has potential glycosylation, phosphorylation, and portals of entry for toxins/viruses/bacteria (16,17), are impor- farnesylation sites. Two conserved amino acid stretches tant for normal synapse density/morphology, and myelin in- within exons 11/13, and two glycosylation sites are neces- tegrity/myelin-axon interactions (18). Composition of HIV sary for antiapoptotic function (2). Membrane topology membranes resembles lipid microdomains supporting raft ex- suggests CLN3p has 5 transmembrane domains with extra- istence in cells (16). Rafts are liquid-ordered microdomains cellular/intraluminal amino- and cytoplasmic/carboxy ter- insoluble in nonionic detergents and derive from Golgi, con- mini (3). sist of glycosphingolipids/cholesterol and are enriched in gly- Received October 25, 2007; accepted January 25, 2008. Correspondence: Rose-Mary N. Boustany, M.D., Abu-Haidar Neuroscience Institute, Abbreviations: ABC transporters, ATP-binding cassette transporters; American University of Beirut, Saab Medical Library Building 3rd Floor, Bliss Street, CLN3, CLN3 gene; CLN3p, CLN3 protein; GalCer, galactosylceramide; Hamra District, Beirut, Lebanon; e-mail: [email protected] GlcCer, glucosylceramide; GLTP, glycolipid transfer proteins; GRASP65, This work was supported by NINDS grant RO-1 N0433344 (to R.-M.N.B) and a grant Golgi reassembly stacking protein; JNCL, Juvenile Neuronal Ceroid Lipo- from the Batten Disease Support and Research Association (to R.-M.N.B.). D.-A.P.-S.’s current address is NIEHS/NIH, Neurobiology/Neurotoxicology Group, fuscinosis; NCL, Neuronal Ceroid Lipofuscinosis; PM, plasma membrane; III TW Alexander Drive, MD C1-04, RTP, NC 27709, USA. RT, room temperature 625 626 RUSYN ET AL. cosylphosphatidylinositol/GPI-anchored proteins (19). They then incubated for 2 h/RT with rabbit anti-GalCer/anti-Glucosylceramide harbor proapoptotic ceramide (20). Prenylated CLN3p pro- (GlcCer) primary Ab (Sigma Chemical Co., Aldrich; St. Louis, MO) at 1:1000 dilution, washed 5ϫ/5min with TBST and incubated with horseradish motes association to LRs (21). These house caspase-8 acti- peroxidase-conjugated anti-rabbit IgG goat antibody for 1 h/RT. After wash- vated in apoptotic CLN3-deficient cells (22). It has been ing, blots are developed in ECL-plus reagent (Amersham Biosciences, Pis- suggested CLN3p contributes to [Delta]-9 desaturase activity, cataway, NJ). Transfection. JNCL of 1 ϫ 106 lymphoblasts are plated in 6-well plates, which targets LR-associated palmitoylated proteins (23). transfected with pGEM-CLN3/empty vector control [Lipofectamine2000 In- CLN3p binding to GalCer in normal cells, and retention of vitrogen (Carlsbad, CA)], then harvested 48 h later, homogenized, and GalCer in Golgi with paucity in rafts of CLN3-deficient cells subjected to subcellular fractionation as outlined above. TLC analysis/lipid mass measurements. Lipids are extracted from 250 is demonstrated. CLN3-deficient rafts exhibit altered sphingo- ␮L/fraction. After methanolysis and measurement of phosphate/protein, samples lipid composition/ultrastructure. When combined, findings are spotted on borate-impregnated TLC-plates and lipids separated with chloro- form/methanol/NH OH 2.5 M (65:35:8). A mixture of standards (Qualmix, suggest that WT CLN3p plays a role in transport of GalCer 4 Matreya, LLC, Pleasant Gap, PA) is used. Sphingolipids are visualized with from endoplasmic reticulum or ER/Golgi to rafts, which is primuline and scanned on a Typhoon-101 scanner. Quantification is accom- impaired in JNCL. Morphologic/biochemical changes are ob- plished with the ImageQuant program. Lipids are normalized to protein. 14 served in CLN1-/CLN2-/CLN6-/CLN8-/CLN9-deficient cells, Gal-labeling. Normal/CLN3-deficient lymphoblasts are labeled with C- galactose (Amersham, Piscataway, NJ) for3dinglucose-free RPMI1640, suggesting that perturbed structure/function of rafts may be a harvested, and subcellular fractionation performed. Protein determination for theme common to these NCLs. fractions is followed by lipid extraction with carriers/base hydrolysis/acid neutralization/lipid reextraction. Dried samples are resuspended and spotted on a TLC plate. Glycosphingolipds are scraped after 2 d. Results are ex- METHODS pressed in counts/min/␮g. Western blot. MAb (flotillin-1/GRASP65/calreticulin) confirm identity of LRs/Golgi/ER fractions, respectively. Fifteen microliter from fractions 1–5 Cell culture. Lymphoblasts are grown at 37°C/5% CO2/RPMI1640 (Sigma Chemical Co., Aldrich, St. Louis, MO)/10% fetal bovine serum and 1% and 5 ␮L from fractions 6–10 are mixed with SDS-PAGE buffer, boiled, and penicillin/streptomycin/Fungizone. Immortalized lymphoblasts from JNCL/ loaded on a 12% polyacrylamide gel. other NCL patients/normal donors and fibroblasts from normal/mnd (CLN8- RNAi knockdown of CGT in normal human lymphoblasts. siRNA is deficient) mice are used. JNCL lymphoblasts are homozygous for the 1.02 kb designed using BLOCK-iT RNA Designer (Invitrogen). Plasmids (1 ␮g) deletion. expressing siRNAs were transfected into normal lymphoblasts. Cells of All cell lines were derived from patient blood and/or skin after obtaining 48–120 h posttransfection are harvested. Conditions (cell density/amount of consent according
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