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Neuronal Ceroid Lipofuscinosis: a Common Pathway?

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Neuronal Ceroid Lipofuscinosis: a Common Pathway? 0031-3998/07/6102-0146 PEDIATRIC RESEARCH Vol. 61, No. 2, 2007 Copyright © 2007 International Pediatric Research Foundation, Inc. Printed in U.S.A. Neuronal Ceroid Lipofuscinosis: A Common Pathway? DIXIE-ANN PERSAUD-SAWIN, TALAL MOUSALLEM, CHRISTINE WANG, ADAM ZUCKER, EIKI KOMINAMI, AND ROSE-MARY N. BOUSTANY Department of Pediatrics [D.-A.P.-S., T.M., C.W., A.Z., R.-M.N.B.], Department of Neurobiology [R.-M.N.B.] Duke University Medical Center, Durham, North Carolina, 27710; Laboratory of Neurobiology/Neurotoxicology [D.-A.P.-S.,], NIEHS/NIH, RTP, North Carolina, 27709; Department of Biochemistry [E.K.], Juntendo University School of Medicine, Tokyo 113-8421, Japan; Abu-Haidar Neuroscience Institute [R.-M.N.B.], American University of Beirut Medical Center, Beirut 1107 2020, Lebanon ABSTRACT: The neuronal ceroid lipofuscinoses are pediatric and 10 y and has mutations in the CLN8 gene. Some Turkish neurodegenerative diseases with common clinical features. Of the vLINCL cases have mutations in the CLN8 gene. nine clinical variants (CLN1–CLN9), six have been genetically A new NCL variant, CLN9, is clinically similar to JNCL. identified. Most variants manifest cell death and dysregulated The gene remains unidentified. Fibroblasts from these patients sphingolipid metabolism, suggesting the proteins defective in grow at accelerated rates and have increased apoptosis and these disorders may interact along one pathway. NCL patient- low ceramide and sphingomyelin levels. derived cell lines exhibit cell growth and apoptotic defects that CLN1 and CLN2 code for the enzymes PPT1 (palmityl reverse following transfection with the wild-type gene. The mem- protein thioesterase 1) and TPP1 (tripeptidyl peptidase 1), brane-bound proteins CLN3, CLN6, and CLN8 complement each respectively. PPT1, a glycoprotein (34 kD), removes long- other, as do CLN1 and CLN2 proteins, with respect to growth and chain fatty acids from cysteine. Its deficiency leads to accu- apoptosis. The CLN2 protein also corrects growth and apoptosis in CLN3-, CLN6-, and CLN8-deficient cell lines. Neither CLN1- mulation of long-chain fatty acid cysteine thioesters. TPP1 (48 deficient nor CLN2-deficient growth defects are corrected by kD) is a lysosomal, serine carboxyl peptidase that removes CLN3, CLN6, and CLN8 proteins. CLN2, CLN3, CLN6, and tri-peptides from oligopeptides. CLN8 proteins co-immunoprecipitate and co-localize to early CLN3, CLN6, and CLN8 are membrane-bound proteins. and/or recycling endosomes and lipid rafts. Additionally, CLN2p The CLN5 protein is a membrane glycoprotein, and the CLN6 and CLN1p co-immunoprecipitate. The work presented supports protein (36 kD monomer, 60 kD dimer) localizes to endoplas- interactions between NCL proteins occurring at multiple points mic reticulum [for review see (1)]. Wild-type CLN3 protein along one pathway. (Pediatr Res 61: 146–152, 2007) (CLN3p, 48–52 kD) traffics from Golgi to lipid rafts at the plasma membrane via Rab4- and Rab11-positive endosomes. CLN3-deficient cells undergo apoptotic/caspase-mediated au- he NCLs (neuronal ceroid lipofuscinosis) are pediatric tophagic cell death (2). CLN3p is neuroprotective and harbors Tneurodegenerative disorders. The nine clinical variants a galactosylceramide (GalCer) lipid raft binding domain sug- are caused by mutations in different genes (CLN1–CLN9). gesting that it may be a GalCer transporter (3). Six of the genes are identified: CLN1, CLN2, CLN3, CLN8 belongs to the TLC family (Tram, Lag1 and CLN8) CLN5, CLN6, and CLN8. These diseases manifest blind- and may impact dihydroceramide synthase (4). CLN8 protein ness, seizures, cognitive and motor decline, and early death. (33 kD) localizes to the ER/ER-Golgi intermediate compart- There is massive neuronal death in the brain. ment (ERGIC). The mouse homolog shares 82–85% sequence INCL (CLN1) sets in before age 2 y. LINCL begins at 1–4 identity with its human counterpart and the mnd mouse is a y and has mutations in the CLN2 gene. Mutations in CLN3 naturally occurring animal model (1). result in JNCL. Symptoms begin between 4 and 10 y. The CLN3-deficient cells have high levels of ceramide/ gene for adult NCL (CLN4, or Kufs disease) is unknown. sphingomyelin that are corrected by CLN3 (5,6). CLN9-defi- cient cells have diminished ceramide/sphingomyelin. Wild- Variant forms of LINCL (vLINCL) include the following: type CLN9 is thought to be an activator of dihydroceramide Finnish variant, with mutations in the CLN5 gene begins at synthase, the enzyme generating dihydroceramide, a ceramide 4–7 y; Portuguese/Costa Rican variant/CLN6 gene, which precursor (7). presents between 18 mo and 8 y; Turkish variant, which Sphingolipids impact cell death, growth, and differentiation manifests between 3 and 7 y, and progressive epilepsy with and are components of lipid rafts, specialized platforms that mental retardation (EPMR), which manifests between ages 5 orchestrate signaling events (8–13). They are implicated in the pathogenesis of neurodegenerative diseases such as Alzhei- Received August 11, 2006; accepted October 6, 2006. mer’s and prion diseases (14). Correspondence: Rose-Mary N. Boustany, M.D., Department of Pediatrics, Research Drive, MSRB 281B, Duke University Medical Center, Durham, NC, 27710; e-mail: [email protected] Abbreviations: CLN1-9, CLN1-9 protein; GalCer, galactosylceramide; INCL, infantile-onset NCL; JNCL, juvenile-onset NCL; LINCL, late infan- DOI: 10.1203/pdr.0b013e31802d8a4a tile-onset NCL; NCL, neuronal ceroid lipofuscinosis 146 NCL PROTEIN INTERACTIONS 147 NCL protein deficiencies result in similar cell biologic incubated with the appropriate secondary antibody at 1:12,000 (CLN1, CLN2, phenotypes including dysregulated cell growth, apoptosis, and and CLN3) or 1:14,000 (CLN6 and CLN8) dilution in block for1hatroom temperature. Membrane was washed and developed with ECLplus (Amer- abnormal sphingolipid/phospholipid levels in CLN1-, CLN2-, sham Pharmacia Biotech, Inc., Piscataway, NJ). CLN3-, CLN6-, and CLN8-deficient cells and neurodegenera- Controls. For newly made antibodies, CLN6 and CLN8 total protein was tion (1). We investigate whether NCL proteins may interact at probed with presera from either antibody to ensure absence of contaminating proteins or nonspecificity. Blots were probed with antibodies to proteins that multiple points along a common pathway. do not bind CLN proteins. For CLN antibodies made in the same host species or similar in size, the membrane used for co-IP was probed once. Antibodies METHODS were presorbed on separate membranes. Antibodies. Antibodies included previously characterized rabbit poly- Cell lines. Fibroblast/immortalized lymphoblast cell lines, derived from clonal anti-CLN3 antibody (3,4), sheep polyclonal anti-CLN6 antibody made normal controls/patients with defects in CLN1, CLN2, CLN3 (JNCL), or to residues 284-301 of the CLN6 protein, sheep polyclonal anti-CLN8 CLN6 genes, were used. Cells from the mnd–/– (mouse cln8) knockout mouse antibody made to residues 2-19 of the CLN8 protein, rabbit polyclonal and its control C57B6 were obtained from the Jackson Labs (Bar Harbor, anti-CLN2 antibody (Orbigen Inc., San Diego, CA), rabbit polyclonal anti- ME). Cos-7 fibroblasts (ATCC, Manassas, VA) were also used. CLN1- CLN1 antibody (gift from Dr. Sandra Hoffman), rat polyclonal anti- deficient cells were kindly provided by Dr. Sandra Hoffman. Cell line GRASP65 antibody (gift from Dr. Francis Barr), goat polyclonal anti-alkaline mutations were CLN1-homozygous R151X, CLN2-homozygous 3556G Ͼ C, phosphatase antibody, goat polyclonal anti-cathepsin D antibody, mouse CLN3-homozygous c.46-677del, and CLN6-homozygous G317G. Use of monoclonal anti-Rab11 antibody, and mouse monoclonal anti-Rab4 antibody patient cells is covered by a Duke University Institutional Review Board– (Research Diagnostics Inc., Concord, MA). Alexa Fluor 488 and 543 secondary approved protocol. antibodies were used (Molecular Probes, Eugene, OR). Tissue culture. Cos-7 and human fibroblasts were grown in Dulbecco’s Co-localization studies. Cells were plated, fixed, and stained as previously modified Eagle’s medium (DMEM) with 10% fetal bovine serum (FBS), described (4). Primary and secondary Alexa Fluor antibodies were added at a lymphoblasts in RPMI 1640 10% FBS, (Invitrogen, Carlsbad, CA) at 37°C 1:1000 dilution and incubated at RT. Cells were imaged with a Zeiss Laser and 5% CO . Mouse cell lines were grown in 20% horse serum. Scanning Confocal Microscope 510 (Carl Zeiss Inc., Thornwood, NY) in 40 2 ␮ ϫ Transfection. cDNA for, CLN1, CLN2, CLN3, CLN6, and CLN8 were Z-planes every 0.1 m from top to bottom of the cell with a 100 oil cloned into pGEM(7ϩ) vector and transfected into cells (2). Fibroblasts were objective. Planes with maximal co-localization were used. Cells from six plated at a density of 1–5 ϫ 104 cells/0.44 cm2. Transfection efficiency was randomly chosen fields of vision were counted and protein distribution assessed with pGEM-YFP fluorescent vector, and was 60–70% for fibroblasts patterns documented. Each experiment was repeated with “no-antibody” and 80–90% for lymphoblasts (p Ͻ 0.05). controls. JC-1 staining and trypan blue dye exclusion assay. Staining with the mitochondrial membrane potential dye, JC-1, and the trypan blue assay are previously described (2). Statistical significance was determined using the t RESULTS test. Propidium iodide staining. Cells were centrifuged, washed, and resus- NCL variants show defective cell growth and increased pended in 100 ␮L PBS, placed on a glass slide, then incubated with 100 ␮L 0.5 mg/mL propidium iodide solution, washed, and viewed using a Leica apoptosis. CLN3-deficient (JNCL) cells have slowed cell fluorescent microscope at 20ϫ magnification. Three hundred cells from three growth and accelerated apoptosis (2). CLN1-, CLN2-, and fields of vision were counted. The t test was applied. CLN6-deficient fibroblasts, and mnd–/– mouse fibroblasts are Co-immunoprecipitation and Western blotting. Cells, 1.5–2 ϫ 106, were snap-frozen at –80°C, thawed, and resuspended in 200–300 ␮L lysis buffer analyzed in this study. CLN1-, CLN2-, CLN3-, and CLN6- [250 ␮L proteinase cocktail inhibitor (Sigma Chemical Co.-Aldrich, St. deficient cells have slowed growth (Fig.
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