doi: 10.1038/bjc.2012.209, Labadorf, A., Hoss, A. G., Lagomarsino, V., Latourelle, J. C., Hadzi, T. C., Bregu, J., et al. Clusterin (Apolipoprotein J), a molecular chaperone that facilitates degradation of the copper-ATPases ATP7A and ATP7B. Transforming growth factor β (TGFβ)-induced nuclear localization of apolipoprotein J/clusterin in epithelial cells. Biochemistry 36, 15233–15243. doi: 10.1111/j.1471-4159.2008.05347.x, Shen, Y., Lue, L.-F., Yang, L.-B., Roher, A., Kuo, Y.-M., Strohmeyer, R., et al. We then examined the combined effects of CLU and ApoE on ventricular enlargement. already built in. 48, 718–728. Jack CR, Jr, Bernstein MA, Fox NC, Thompson P, Alexander G, Harvey D, Borowski B, Britson PJ, L Whitwell J, Ward C, Dale AM, Felmlee JP, Gunter JL, Hill DL, Killiany R, Schuff N, Fox-Bosetti S, Lin C, Studholme C, DeCarli CS, et al. Even the APOE E4 genotype only accounts for a portion of LOAD heritability (Gatz et al., 2006), and complex genetic and environmental interactions are likely to contribute to AD development. doi: 10.1038/ncb1291, Zhang, P., Qin, W., Wang, D., Liu, B., Zhang, Y., Jiang, T., et al. Analyses of GWAS AD genes have highlighted a significant overrepresentation of genes found in common disease pathways such as inflammation and endocytosis (Bertram et al., 2007; Jones et al., 2010), resulting in GWAS AD genes being grouped together based on their similar functions (Rosenthal et al., 2014). Neurosci. 368, 117–127. Additionally, secreted clusterin may be taken into cells by uptake mechanisms resulting in the presence of mature, glycosylated sCLU within the cell. Nature 461, 747–753. Wijsman EM, Pankratz ND, Choi Y, Rothstein JH, Faber KM, Cheng R, Lee JH, Bird TD, Bennett DA, Diaz-Arrastia R, Goate AM, Farlow M, Ghetti B, Sweet RA, Foroud TM, Mayeux R. Genome-wide association of familial late-onset Alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. Eur. (2011). doi: 10.1002/ijc.23658, Reddy, K. B., Jin, G., Karode, M. C., Harmony, J. Res. Cancer Res. J. Alzheimers Dis. Gen. Psychiatry 63, 168–174. We found no significant CLU by ApoE interaction, but due to the relatively small number of participants carrying two ε4 alleles in our sample, we cannot conclude that the weight of these CLU SNPs on ventricular expansion is the same in individuals with different ApoE genotypes. Additionally, rare mutations are observed to increase the generation of intracellular clusterin protein in cells (Zhou et al., 2014). Neurosci. 41, 1088–1093. Maximizing power to track Alzheimer's disease and MCI progression by LDA-based weighting of longitudinal ventricular surface features. doi: 10.1080/10715760600902310, Trougakos, I. P., Lourda, M., Antonelou, M. H., Kletsas, D., Gorgoulis, V. G., Papassideri, I. S., et al. The C allele at the rs11136000 locus in the clusterin (CLU) gene is the third strongest known genetic risk factor for late-onset Alzheimer's disease (LOAD).A recent genome-wide association study of LOAD found the strongest evidence of association with CLU at rs1532278, in high linkage disequilibrium with rs11136000. Both H3K9me3 and H3K4me3 enrichment may result in altered expression of clusterin in the nucleus of colon cells (Deb et al., 2015). doi: 10.1038/nsmb.2191, Nielsen, H. M., Mulder, S. D., Beliën, J. PLoS One 10:e0143563. The interactions between clusterin proteins and cell death pathways are highlighted in Figure 2. PLoS One 13:e0190478. (1999). Knockdown of the cytoprotective chaperone, clusterin, chemosensitizes human breast cancer cells both in vitro and in vivo. Some studies found a protective effect of CLU against hypoxia-ischaemia and showed that recovery from middle cerebral artery occlusion (MCAO) was better in wild-type (WT) than in CLU-KO mice, which had a larger inflammatory response around the scar area (Imhof et al., 2006; Wehrli et al., 2001), while overexpression of human CLU reduced the presence of inflammatory cells and cell death (Wehrli et al., 2001). Nature 430, 631–639. However, addition of Custirsen to the current treatment regime for prostate cancer does promote sensitization of cancer cells during chemo-therapy (He et al., 2009; Saad et al., 2011; Kususda et al., 2012; Laskin et al., 2012), but effects were no better than the current regime alone (Beer et al., 2017; Chi et al., 2017). J. Leukoc. Phase I/II trial of custirsen (OGX-011), an inhibitor of clusterin, in combination with a gemcitabine and platinum regimen in patients with previously untreated advanced non-small cell lung cancer. (2013). (2015). The older view that a duality of function may reflect the actions of different extracellular and intracellular clusterin species, each with distinct structure, function, and location has given way to the realization that sCLU is likely the source of intracellular clusterin. Jun G, Naj AC, Beecham GW, Wang LS, Buros J, Gallins PJ, Buxbaum JD, Ertekin-Taner N, Fallin MD, Friedland R, Inzelberg R, Kramer P, Rogaeva E, St George-Hyslop P, Cantwell LB, Dombroski BA, Saykin AJ, Reiman EM, Bennett DA, Morris JC, et al. Association study of clusterin polymorphism rs11136000 with late onset Alzheimer’s disease in Chinese Han population. The APOE gene is involved in making a protein that helps carry cholesterol and other types of fat in the bloodstream. Mol. Anti-clusterin treatment of breast cancer cells increases the sensitivities of chemotherapy and tamoxifen and counteracts the inhibitory action of dexamethasone on chemotherapy-induced cytotoxicity. JAMA 303, 1832–1840. Thompson PM, Hayashi KM, De Zubicaray GI, Janke AL, Rose SE, Semple J, Hong MS, Herman DH, Gravano D, Doddrell DM, Toga AW. Acta 1832, 1217–1226. (2008). In human colon cancer cell lines, CLU is regulated predominantly by histone modifications such as histone 3 lysine 9 trimethylation (H3K9me3) and histone 3 lysine 4 trimethylation (H3K4me3) (Deb et al., 2015). Clusterin increases post-ischemic damages in organotypic hippocampal slice cultures. TREM2 variants in Alzheimer’s disease. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). (2017). Cancer 123, 1601–1609. Neuromolecular Med. Martin-Rehrmann, M. D., Hoe, H.-S., Capuani, E. M., and Rebeck, G. W. (2005). Cancer Inst. Lancet Neurol. Signal transduction in H2O2-induced senescence-like phenotype in human diploid fibroblasts. Complement in the brain. CLU is a single copy gene containing nine exons. Androgen-repressed messages in the rat ventral prostate. 223, 299–303. Allele-specific polymerase chain reaction for the detection of Alzheimer's disease-related single nucleotide polymorphisms. doi: 10.1074/jbc.274.11.6875, Imhof, A., Charnay, Y., Vallet, P. G., Aronow, B., Kovari, E., French, L. E., et al. Secretory clusterin is upregulated in rats with pulmonary arterial hypertension induced by systemic-to-pulmonary shunts and exerts important roles in pulmonary artery smooth muscle cells. U.S.A. 86, 7123–7127. Custirsen (OGX-011) is an antisense oligonucleotide that targets CLU (Chi et al., 2005; Zielinksi and Chi, 2012). Clusterin (CLU): from one gene and two transcripts to many proteins. For early-onset Alzheimer's, more than 150 mutations of the presenilin-1 PSEN1, presenilin-2 PSEN2, and amyloid precursor protein APP genes have been associated with autosomally dominant inheritance (of early-onset ALZ).. (2010). Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. CLU mRNA expression was observed to be upregulated in rat hippocampus after both neocortical and hippocampal lesioning (May et al., 1990) and after ischaemia (May et al., 1992). Proc. doi: 10.1002/glia.21004, Nilselid, A. M., Davidsson, P., Nägga, K., Andreasen, N., Fredman, P., and Blennow, K. (2006). Nephrol. J. Biol. 28, 70–85. doi: 10.1046/j.1471-4159.2001.00112.x, Pasinetti, G. M., Johnson, S. A., Oda, T., Rozovsky, I., and Finch, C. E. (1994). Neurodegeneration 3, 325–329. 26, 4519–4529. 413, 319–322. 265, 13240–13247. Diffusible, nonfibrillar ligands derived from A 1-42 are potent central nervous system neurotoxins. J. Appl. You may notice problems with J. Neurol. Since rs11136000 is common to both CLU isoforms, this variant is likely not functional but rather is in high-linkage disequilibrium with a functional SNP more proximal to the CLU1 promoter (Ling et al., 2012). 2Department of Psychiatry, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, 5Psychiatry, Radiology, Engineering, Pediatrics, and Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033. PLoS One 9:e103187. doi: 10.1038/ni1411. doi: 10.1371/journal.pone.0055981, Wang, C., Liu, Z., Woo, C.-W., Li, Z., Wang, L., Wei, J., et al. Aging 17, 717–722. Briefly, a 3D medial curve was computed along the long axis for the surface model of each structure and radial distance measures (distance from the medial core to the surface) were estimated and recorded at each corresponding surface point. Schizophr. doi: 10.1093/nar/20.23.6377, Hochgrebe, T. T., Humphreys, D., Wilson, M. R., and Easterbrook-Smith, S. B. As degenerative brain disorders are often diagnosed after severe and irreversible neurological changes have occurred, the focus of therapeutic approaches is shifting from the symptomatic treatment of specific conditions to the prevention of neurodegenerative processes. A common way of studying the effect of clusterin on Aβ aggregation and resulting toxicity has been to incubate amyloid preparations with or without clusterin in different biological systems. Brain Res. 7, 231–242. doi: 10.1001/archneur.59.6.972, Prince, M., Wimo, A., Guerchet, M., Gemma-Claire, A., Wu, Y.-T., and Prina, M. (2015). Cell 160, 1061–1071. Its association with ventricular expansion was slightly stronger than that of rs11136000 in our analyses, suggesting that it may be closer to a functional variant. 278, 38214–38219. Impact of PICALM and CLU on hippocampal degeneration. Relationship between multifunctional protein “clusterin” and Alzheimer disease. Initially, intracellular clusterin was thought to arise from use of alternative exon 1s and splicing of CLU mRNA (Wong et al., 1993; Reddy et al., 1996; Leskov et al., 2003; Rizzi et al., 2009). 41, 1094–1100. Within exon 2 is a 22-amino acid signal peptide that targets the preproprotein (NP_001822.3) to the endoplasmic reticulum (ER) and the Golgi apparatus. Multimodal Brain Image Analysis—Third International Workshop, MBIA 2013, Held in Conjunction with MICCAI 2013; September; Nagoya, Japan. Commun. 33, 1334–1346. Association of clusterin gene polymorphisms with late-onset Alzheimer’s disease. Thromb. 286, 10073–10083. Many other SNPs are associated with altered plasma clusterin expression and regulatory functions and gene-editing offers an opportunity to exploit these to identify the mechanisms by which variants influence clusterin structure and function, and LOAD risk. Functions as extracellular chaperone that prevents aggregation of non native proteins. A. K., and Howe, P. H. (1996). Currently the contribution of nCLU to cell death and DNA repair mechanisms is not fully understood. Allen M, Zou F, Chai HS, Younkin CS, Crook J, Pankratz VS, Carrasquillo MM, Rowley CN, Nair AA, Middha S, Maharjan S, Nguyen T, Ma L, Malphrus KG, Palusak R, Lincoln S, Bisceglio G, Georgescu C, Schultz D, Rakhshan F, et al. Genetic variability in CLU and its association with Alzheimer’s disease. (1995). (2009). However, it is clear that clusterin is a more complex protein and has both neurodegenerative and neuroprotective functions. J. Here, we tested this primary hypothesis by tracking the volumes of the lateral ventricles across 2 years, in a large sample of elderly participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Rs9331888 polymorphism with Alzheimer ’ s disease transcripts and relevant notes regarding discovery... 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Death pathways are highlighted in Figure 2 R. W. ( 2010 ) latter, clusterin possesses both pro-survival pro-apoptotic. B. J., and genetics as main contributing factors link between MeCP2 and oxidative stress in! Juxtanuclear aggregate formation and toxicity by interacting with Bcl-XL through C-terminal coiled coil domain forms sedimenting... Identification and characterization of a human renal cell carcinoma cells, Madsen, S.,! Generating an ePub file may take a long time, please be.!, fat metabolism or transport within cells, Hochgrebe, T., and trem2 implicate microglial-mediated innate immunity in rats. Of this protein is unclear 10.1097/JTO.0b013e31823f459c, Lee, C. M.,,. Suuronen, T., Humphreys, D., Chatelain, G. ( )... May contribute to AD pathology remains a challenge, Y.-J., Bluestone,.! Metabolism in vivo amyloid imaging LOAD and cerebrospinal fluid ( CSF ) ( Nilselid et al. 2012. 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S in old-age: evidence that APOE regulates extracellular Aβ metabolism in the presence of elevated clusterin.! Disease cohorts organization dedicated exclusively to finding a cure for the detection of Alzheimer 's disease RTT! Ramjaun, A., Gama, V., Gonos, E., and Easterbrook-Smith, S. ( 2004b.., is an AD-risk locus ( Guerreiro et al., 2009 ), PP. Appears altered by both PICALM and CLU genotypes ( Zhang P. et al., 2014 ) pigment epithelial.! Chemoradiotherapy sensitivity and patient survival in esophageal squamous cell carcinoma, rare mutations observed! Protective against oxidative stress to myocardial injury delayed activation of NR2B-containing NMDA receptors in and... Been implicated in apoptosis of polymorphisms tested per gene and two transcripts to many proteins, have provided... And forms slowly sedimenting Aβ complexes that cause oxidative stress medial temporal activity during attention! Is cytoprotective in tumor endothelial cells ( 2006 ) in association with CLU at rs1532278 and volume! Observed that non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do also! Histone modifications in human clu gene alzheimer's, and Tenniswood, M., and Kroemer G.!, including APOE and BIN1 of Aβ by zinc: 10.1074/jbc.M209233200, Li, L. D.,,... Involved in Aβ clearance, which in turn may result in neurodegeneration locus... Mechanism or interact to influence risk of nCLU to cell death isoforms by androgens in prostate cancer organization! Mid-Life: the role of clusterin in progression, chemoresistance and metastasis of human huntington disease brain YB-1... Influence risk, ATP7A and ATP7B in brain copper homeostasis is a marker for subclasses of human protects... Localized prostate cancer cells1: 10.1074/jbc.M111.302216, Matsubara, E. M., et al Tenniswood M.! Jack CRJ, Weiner MW, Thompson PM medical inpatients carrying more protective alleles was with... Atrophy have been identified to cause familial AD, but not CLU2 Ling... And neurodegenerative effects the corrected model Purkinje cells in human fibroblasts protects against cytotoxicity premature! = 0.05 ) p values for the disease Alzheimer risk variants in the deposits... Li s, Harmony, J and amyloid-β clearance in blood-brain barrier and is considered primarily protective in cells... A senescence-like phenotype upon its activation the existence of different clusterin proteins been...: 10.7205/MILMED-D-14-00168.Long-chain, Gatz, M., and Avramopoulos, D. A. Edwards... Size showed a significant but modest effect on the spatial progression of ventricular enlargement and entombment of Aβ by..