(2010). Heart Fail. doi: 10.1038/nm0901-977, Wei, L., Xue, T., Wang, J., Chen, B., Lei, Y., Huang, Y., et al. Data used in this study were obtained from the ADNI database. Sustained astrocytic clusterin expression improves remodeling after brain ischemia. (2009). CLU rs9331888 polymorphism contributes to Alzheimer’s disease susceptibility in caucasian but not east asian populations. APOE4 Gene and Alzheimer’s Disease. Apolipoproteins E and J interfere with amyloid-beta uptake by primary human astrocytes and microglia in vitro. Mol. Maps in Figures 1 and ​and22 were corrected for multiple comparisons using a false discovery rate (FDR) of 5% (q value = 0.05). For example, both APOE and CLU bind lipids and cholesterol to influence their trafficking, while clusterin and CR1 are regulators of the immune response. CLU is highly influenced by stress; the AP-1 binding site responds to several stress-related transcription factors including TGF-β (Herault et al., 1992; Wong et al., 1993; Jin and Howe, 1997), which reduces CLU expression (Jin and Howe, 1997) through the induction of c-fos (Marti et al., 1994; Jin and Howe, 1997, 1999; Itahana et al., 2007). However, results from different studies are inconsistent. Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts. Furthermore, in the AD entorhinal cortex, clusterin co-localized with neurofibrillary tangles (NFTs), and neurons containing NFTs showed increased expression of CLU (Dunckley et al., 2006). It is also unclear whether they have a shared mechanism or interact to influence risk. Genotype at the rs11136000 and rs1532278 loci was not significantly related to total ventricular volume at baseline (p = 0.276 and p = 0.203, respectively), after controlling for sex, age, and diagnosis (N = 736). In this review, we discuss the complexity of clusterin and the importance of this protein in the context of neurodegenerative diseases while drawing parallels from other fields, particularly, oncology. Ann. Acta Physiol. Oncol. Essential requirement of apolipoprotein J (clusterin) signaling for IκB expression and regulation of NF-κB activity. doi: 10.3233/JAD-2011-111844, Xiu, P., Dong, X., Dong, X., Xu, Z., Zhu, H., Liu, F., et al. ADNI participants were genotyped using the Illumina 610-Quad BeadChip. Rs11136000 was considered to be the main CLU SNP that altered AD risk (Harold et al., 2009; Lambert et al., 2009). (2018). Free Radic. Clusterin may also act as an anti-oxidant in the heart (Mackness et al., 1997), a function that appears dependent on the phosphorylation of Akt/GSK-β and PI3K pathways (Jun et al., 2011; Liu et al., 2015). doi: 10.1093/hmg/ddq142, Bettens, K., Vermeulen, S., Van Cauwenberghe, C., Heeman, B., Asselbergh, B., Robberecht, C., et al. Clusterin as a predictor for chemoradiotherapy sensitivity and patient survival in esophageal squamous cell carcinoma. CLU also appears to be controlled epigenetically. Chem. Late-onset Alzheimer risk variants in memory decline, incident mild cognitive impairment and Alzheimer disease. 31, 18180–18184. Nature 461, 747–753. (2009). Astrocytic Aβ1-42 uptake is determined by Aβ-aggregation state and the presence of amyloid-associated proteins. Cell Stress Chaperones 15, 115–121. Glycosylation occurs at 6 sites (indicated in red) on both the β-chain (sites 86, 103, and 145) and the α-chain (sites 291, 354, and 374). Rev. (1983). Apoptotic activator p53 represses CLU promoter activity and transcription in the MCF-7 breast cancer and the HCT 116 colon cancer cell lines, resulting in reduced levels of secreted clusterin (Criswell et al., 2003). Nat. Zlokovic BV. Transport pathways for clearance of human Alzheimer’s amyloid β-peptide and apolipoproteins E and J in the mouse central nervous system. Thromb. This was not influenced by APOE E4 genotype and regardless of dementia status. doi: 10.1038/onc.2012.212, Li, X., Ma, Y., Wei, X., Li, Y., Wu, H., Zhuang, J., et al. A recent study using N2a mouse neuroblastoma cultures and in vivo Drosophila models of ALS showed that CLU overexpression reduces TDP-43 protein aggregation and toxicity (Gregory et al., 2017). J. Biochem. (2015). Two phosphorylation sites are also known (indicated in pink) at residues 133 and 396. Numerous studies have shown that the knockdown of CLU increases cell sensitivity to chemotherapy drugs and enhances cell death (Viard et al., 1999; Lee et al., 2002; Trougakos et al., 2004; So et al., 2005; Redondo et al., 2007). The rs11136000 variant was identified simultaneously in two independent genome-wide association studies (GWASs; Harold et al., 2009; Lambert et al., 2009), and was later replicated in other GWAS (Wijsman et al., 2011) and case-control studies (Carrasquillo et al., 2010; Jun et al., 2010), though the newest GWAS found the strongest evidence of association with CLU at rs1532278 (Naj et al., 2011). To construct a surface boundary for each new subject, a normalized similarity measure (mutual information) between each template image and the new image was computed around each vertex point of each deformed template surface. (2013). (2013). (2014). Finally, mature secreted clusterin (sCLU) is produced and secreted from cells. Biophys. doi: 10.1074/jbc.M206428200, O’Sullivan, J., Whyte, L., Drake, J., and Tenniswood, M. (2003). 286, 10073–10083. 28, 53–69. (2009) similarly observed a significant association between CLU SNP rs11136000 and AD, and this was further replicated in another GWAS (Seshadri et al., 2010) and in smaller Caucasian and European cohorts (Carrasquillo et al., 2010; Naj et al., 2011; Shuai et al., 2015; Zhang S. et al., 2015, 2016; Zhu et al., 2017). However, the reports of multiple CLU mRNA transcripts (outlined in Table 1) were interpreted as a differential transcriptomic origin of intracellular and secreted clusterin proteins (Reddy et al., 1996; Schepeler et al., 2007). Biophys. Acad. doi: 10.1158/0008-5472.CAN-03-2664, Urban, J., Parczyk, K., Leutz, A., Kayne, M., and Kondor-Koch, C. (1987). J. Additionally, clusterin has been more recently identified as a mediator of Aβ toxicity, as evidenced by the neuroprotective effect of CLU knockdown and knockout in rodent and human iPSC-derived neurons. doi: 10.1021/bi002189x, Praticò, D., Clark, C. M., Liun, F., Lee, V. Y.-M., and Trojanowski, J. Q. US researchers say that the CLU gene, a known Alzheimer risk factor, can begin to damage the brain a full 50 years before the disease actually sets in. The C risk allele at rs11136000 is associated with lower CLU expression (Allen et al., 2012; Ling et al., 2012), reflecting decreased soluble, secreted clusterin protein throughout life (Ling et al., 2012). Commun. No use, distribution or reproduction is permitted which does not comply with these terms. Plaques formed in the absence of CLU displayed decreased surrounding neuritic dystrophy, which argued in favor of a pro-amyloidogenic role of clusterin in this mouse model (DeMattos et al., 2002). 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. Laminar shear stress upregulates the complement-inhibitory protein clusterin. 4, 123–133. 31:73. doi: 10.1186/1756-9966-31-73, Tarasoff-Conway, J. M., Carare, R. O., Osorio, R. S., Glodzik, L., Butler, T., Fieremans, E., et al. doi: 10.1002/pros.2990080105, Moretti, R. M., Marelli, M. M., Mai, S., Cariboni, A., Scaltriti, M., Bettuzzi, S., et al. Metalloenzyme-like activity of Alzheimer’s disease β-amyloid: cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. Copper, iron and zinc in Alzheimer’s disease senile plaques. Extensive genetic studies have identified genes that alter AD risk and numerous SNPs have also been identified associated with these genes (Bertram et al., 2007; Bertram and Tanzi, 2009; Harold et al., 2009; Lambert et al., 2009, 2013; Seshadri et al., 2010). (2008). 35, 878–893. In a sense, the less commonly carried version of CLU—the minor T allele—may be considered a protective form of the gene. The exact mechanisms by which these genes influence AD risk are unclear. The genes -- which are called CLU… Acad. Non-secreted clusterin isoforms are translated in rare amounts from distinct human mRNA variants and do not affect bax-mediated apoptosis or the NF-κB signaling pathway. (2015). Exp. Muscle cells after vascular injury. (2011). A large part of the challenge in understanding the role of clusterin in disease arises from the complexity of its biogenesis that results in multiple protein species associated with distinct cellular functions. Polymorphisms of CR1, CLU and PICALM confer susceptibility of Alzheimer’s disease in a southern Chinese population. The CLU gene is one of the prime genetic candidates associated with Alzheimers disease. U.S.A. 86, 7123–7127. PICALM-AG and CLU-CC showed a trend for improvement in memory which only reached significance when APOE E3 was present (Barral et al., 2012), highlighting that different genotype combinations at three AD genes produce different effects on a measurable phenotype that is AD-relevant. doi: 10.1111/j.1432-1033.1994.tb18807.x, Xie, D., Sze, H. L., Sham, J. S. T., Wu, Q. L., Fang, Y., Liang, L. Z., et al. Similarly, co-culture experiments on rat hippocampal astrocytes and neurons showed that clusterin incubation prevents Aβ-induced astrocytic calcium uptake, resulting in decreased ROS generation and caspase 3 activation; additionally, clusterin blocked Aβ-induced inhibition of LTP on hippocampal slices (Narayan et al., 2014). (2012) showing that clusterin is able to bind a wide range of Aβ oligomers (from dimers to 50-mers), and consequently to prevent further aggregation into fibrils. Thromb. GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer. The template surfaces were registered into homologous point-to-point correspondence as a group using medial-spherical registration (Gutman et al., 2012). Neuromolecular Med. (2012). doi: 10.1093/hmg/ddw188, Kang, S. W., Shin, Y. J., Shim, Y. J., Jeong, S. Y., Park, I. S., and Min, B. H. (2005). 50, 540–547. Nature 430, 631–639. 27, 250–257. Amphiphysin heterodimers: potential role in clathrin-mediated endocytosis. Chou YY, Leporé N, de Zubicaray GI, Carmichael OT, Becker JT, Toga AW, Thompson PM. N. Engl. ApoE genotyping is considered valuable in clinical trials for Alzheimer's disease and mild cognitive impairment, but growing evidence for both independent CLU effects on brain structure and function and combined effects of CLU and ApoE affecting neurodegenerative processes and the trajectory of brain atrophy, suggest that genotyping these CLU variants may empower clinical trials of dementia. Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, Pahwa JS, Moskvina V, Dowzell K, Williams A, Jones N, Thomas C, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, et al. Clusterin and APOE are both members of the apolipoprotein family of proteins, binding to lipids and cholesterol to promote their transport and processing, an important part of their homeostasis (Mahley, 1988; De Silva et al., 1990). doi: 10.1074/mcp.M600261-MCP200, Atagi, Y., Liu, C.-C., Painter, M. M., Chen, X.-F., Verbeeck, C., Zheng, H., et al. 8:779. doi: 10.3389/fnhum.2014.00779, Du, W., Tan, J., Xu, W., Chen, J., and Wang, L. (2016). Pharmaceutical agents such as valproate, which counteract the effects of genetically determined reduced clusterin expression, may help to achieve neuroprotection and contribute to the prevention of dementia, especially in carriers of these CLU risk variants. Pathways towards and away from Alzheimer’s disease. Astrocytes and microglia are both implicated in capturing and eliminating Aβ from the brain interstitial fluid (ISF) (Tarasoff-Conway et al., 2015). J. doi: 10.2217/fon.12.129, Zinkie, S., Gentil, B. J., Minotti, S., and Durham, H. D. (2013). 258, 7714–7720. Genetic polymorphisms of clusterin gene are associated with a decreased risk of Alzheimer’s disease. As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data, but most of them did not participate in this analysis or the writing of this report. 7, 909–915. (2012). doi: 10.1016/0197-4580(92)90086-D, Jones, L., Holmans, P. A., Hamshere, M. L., Harold, D., Moskvina, V., Ivanov, D., et al. doi: 10.1371/journal.pone.0058618, Miyata, M., Biro, S., Kaieda, H., Eto, H., Orihara, K., Kihara, T., et al. 104, 375–382. doi: 10.1152/japplphysiol.00681.2002, Cao, C., Shinohara, E. T., Li, H., Niermann, K. J., Kim, K. W., Sekhar, K. R., et al. Ling et al. Oncogene 9, 1213–1223. doi: 10.1038/sj.cdd.4401254, Padhy, B., Hayat, B., Nanda, G. G., Mohanty, P. P., and Alone, D. P. (2017). Neurodegener. Science 261, 921–923. Genet. (2005). The genetic landscape of Alzheimer disease: clinical implications and perspectives. 280, 14212–14221. 25, 95–98. Liu, L., Lioudyno, M., Tao, R., Eriksson, P., Svensson, M., and Aldskogius, H. (1999). Rs9331896, also an intronic SNP, was identified by Lambert et al. The very complexity of clusterin function may prove to be beneficial in identifying downstream pathways and searching for potential therapeutic targets that distinguish between its pro-apoptotic and anti-apoptotic actions. Clusterin expression in normal mucosa and colorectal cancer. CLU is now considered the third greatest genetic risk factor for LOAD, after APOE and BIN1. Roussotte et al. 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). BIN1 interacts with tau protein and its main influence on AD risk is in the modulation of tau pathology (Chapuis et al., 2013). (2015). All of this underlies the potential importance of functional links between multiple risk genes in disease mechanism (see section “Relationships to Other AD Genes”). 107, 341–346. Longitudinal stability of MRI for mapping brain change using tensor-based morphometry. Rep. 6:26027. doi: 10.1038/srep26027, Tang, Y., Liu, F., Zheng, C., Sun, S., and Jiang, Y. Clusterin expression by astrocytes is influenced by transforming growth factor β1 and heterotypic cell interactions. However, it is clear that clusterin is a more complex protein and has both neurodegenerative and neuroprotective functions. Genome-wide analysis of genetic loci associated with Alzheimer’s Disease. Biochim. Carmichael OT, Kuller LH, Lopez OL, Thompson PM, Dutton RA, Lu A, Lee SE, Lee JY, Aizenstein HJ, Meltzer CC, Liu Y, Toga AW, Becker JT. Alzheimer’s disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. Nevertheless, a common finding is that clusterin interferes with Aβ aggregation, in agreement with observations from Narayan et al. Oncogene 23, 2298–2304. The inflammatory component of AD is an area under intense study, and it is clear that glial responses to protein aggregation contribute to AD pathogenesis (Heneka et al., 2015); however, the potential neuro-inflammation regulatory role of clusterin in AD has not been studied in depth. 11, 457–470. Neurobiol. Association between clusterin gene polymorphism rs11136000 and late–onset Alzheimer’s disease susceptibility: a review and meta–analysis of case–control studies. Acta 1852, 1630–1645. (2012) described a preferential effect of the T allele of rs11136000 on a single CLU mRNA transcript and commented that the protective T allele of rs11136000 is associated with an increased expression of one CLU transcript, which may reflect higher sCLU protein levels throughout life that may provide protection. Nucleic Acids Res. Med. 39, 137–152. Res. (2010), except that ours is based on surface geometry rather than image voxels. The ePub format is best viewed in the iBooks reader. Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. Additionally, our group also observed that treatment of rodent primary neurons with Aβ leads to reduced clusterin secretion and increased intracellular clusterin (Killick et al., 2014). GWAS have now identified several genes that alter LOAD risk including, among others, bridging integrator 1 (BIN1) and CLU, which are the second and third most common genetic risk factors after APOE1. Br. J. Biol. 122, 433–439. Mol. Role of extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats. (2007). It will be important for AD research to identify the source of neuronal intracellular clusterin. 268, 5021–5031. (1997). 265, 13240–13247. Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. Two Alzheimer’ disease risk genes increase entorhinal cortex volume in young adults. Neurosci. Urology 60, 516–520. Oncology research has highlighted the opposing roles of clusterin proteins in cell death and survival, presenting the same apparent contradiction as seen in neurodegeneration. Int. Brain Res. Mol. Mutations in genes such as PSEN1, PSEN2, and APP result in the rare, familial, early onset forms of AD, while over 20 genes have been identified that influence the risk of the more common, sporadic, late onset AD (LOAD) (Van Cauwenberghe et al., 2016). J. Radiat. Results of multiple regression analyses: combined effects of CLU (rs11136000) and ApoE genotypes on ventricular volume expansion. Cancer Res. Association of the Alzheimer’s disease clusterin risk allele with plasma clusterin concentration. This brings into sharp focus the relevance of understanding how intracellular clusterin arises in cells, the structural differences and similarities between secreted and intracellular clusterin, and how these contribute to pathophysiological events. Hippocampal function in healthy carriers of the CLU Alzheimer’s disease risk variant. Transforming growth factor β (TGFβ)-induced nuclear localization of apolipoprotein J/clusterin in epithelial cells. Cell Biol. (2006). 309, 305–315. 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. So, do these observations of diverse disease states provide any gestalt perspective of clusterin function? Intriguingly, the more prevalent form of this variant—the major C allele—confers greater AD risk. Neurosci. Additionally, the demonstration that CLU silencing provides protection from Aβ-induced neurotoxicity in rodent neurons and iPSC-neurons (Killick et al., 2014; Robbins et al., 2018) also points to the importance of altered distribution of clusterin across the cell and clusterin’s pathological role in mediating Aβ toxicity in neurons. (2014). The CLU-files: disentanglement of a mystery. (2008). Semen clusterin is a novel DC-SIGN ligand. 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). Cancer Biol. Apolipoprotein E4 polymorphism as a genetic predisposition to delirium in critically ill patients. J. Biol. doi: 10.1007/s12192-009-0122-0. |, Clusterin Complexity: From Gene to Protein, Bibliography Search and Selection Criteria, Creative Commons Attribution License (CC BY), Department of Psychiatry, University of Oxford, Oxford, United Kingdom. 67, 961–964. doi: 10.1016/j.yexcr.2006.12.010, James, R., Hochstrasser, A., Borghini, I., Martin, B., Pometta, D., and Hochstrasser, D. (1991). Hypoxia-ischaemia brain insult also triggers CLU expression (Zoli et al., 1993; Yasuhara et al., 1994; Walton et al., 1996; Kurian and McGuone, 2012). Physiol. Multiple strands of evidence suggest that intracellular clusterin is a modified form of secreted clusterin. doi: 10.1016/j.jalz.2016.03.001, Ammar, H., and Closset, J. L. (2008). MCI patients show increased plasma clusterin in the presence of rs11136000-C allele, which negatively correlates with cognitive function scores (Cai et al., 2016). Exp. The ADNI cohort included the following three diagnostic groups: subjects with AD, subjects with amnestic MCI, and healthy elderly control (CON) subjects (Aisen et al., 2010). (2009). Based on 622 phantom scans collected at 49 sites, the average SDs of scale factors across individual scanners were 0.04%, 0.07%, and 0.11% along the x-, y-, and z-axes, respectively (Gunter et al., 2007). doi: 10.1111/j.1471-4159.2008.05519.x, Hallström, T., Uhde, M., Singh, B., Skerka, C., Riesbeck, K., and Zipfel, P. F. (2015). Clusterin (CLU) or APOJ is a multifunctional glycoprotein that has been implicated in several physiological and pathological states, including Alzheimer’s disease (AD). (2010). We analyzed two common (C > T, minor allele frequency: T = 0.385 for rs11136000; and T = 0.281 for rs1532278) single nucleotide polymorphisms (SNPs) in the CLU gene, for association with longitudinal ventricular expansion and ventricular surface morphology, independently of dementia status. Neurol. Recent genome wide association studies found links for sporadic AD with CLU and CR1 involved in Aβ clearance, and PICALM affecting intracellular trafficking. Cancer Ther. 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. Subsequently, we examined the combined effects of CLU and ApoE genotypes by comparing the trajectory of ventricular volume expansion between carriers of at least one protective allele at both loci (0 or 1 ApoE-ε4 allele and 0 or 1 C allele at rs11136000/rs1532278), carriers of at least one protective allele at either locus (0 or 1 ApoE-ε4 allele or 0 or 1 C allele at rs11136000/rs1532278), and participants with two risk alleles at both loci (2 ApoE-ε4 alleles and 2 C alleles at rs11136000/rs1532278). doi: 10.1016/S0169-328X(03)00124-4, Wilson, M. R., and Easterbrook-Smith, S. B. J. Biol. Several mechanisms of brain Aβ clearance have been described, including intracellular uptake and transport across the BBB (Tarasoff-Conway et al., 2015), both of which have implications for the role of clusterin in AD. Mol. 25, 421–424. Characterization of four lipoprotein classes in human cerebrospinal fluid. Generating an ePub file may take a long time, please be patient. 9:R86. doi: 10.1016/j.expneurol.2009.07.033, Zhou, Y., Hayashi, I., Wong, J., Tugusheva, K., Renger, J. J., and Zerbinatti, C. (2014). doi: 10.1523/JNEUROSCI.4562-11.2012, Qiu, L., He, Y., Tang, H., Zhou, Y., Wang, J., Zhang, W., et al. 11, 352–372. Association analysis between the rs11136000 single nucleotide polymorphism in clusterin gene, rs3851179 single nucleotide polymorphism in clathrin assembly lymphoid myeloid protein gene and the patients with schizophrenia in the Chinese population. In most cases, little is known about how these SNPs influence mRNA and protein expression of clusterin and no functional variant has yet been identified. However, this interference with Aβ aggregation has been observed to influence toxicity of the amyloid products in differing ways. (1995). Apolipoprotein J and Alzheimer’s amyloid beta solubility. 5:5775. doi: 10.1038/ncomms6775, Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O’Keeffe, S., et al. The C allele confers an increased risk of 1.16-fold to AD (Bertram et al., 2007) and is carried by 88% of Caucasians (Lambert et al., 2009). This is accompanied by a reduction in anti-apoptotic proteins, including Bcl-2, resulting in cells becoming more vulnerable to the pro-apoptotic effects of BAX (Trougakos et al., 2009). Cancer Sci. Hum. Much of the subsequent focus over the last thirty years has been driven by the discoveries of elevated levels of clusterin in the AD brain, its ability to bind Aβ peptides and the latter discovery of clusterin genetic variants as AD risk factors. Acta Neuropathol. Neurosci. Neurosci. doi: 10.1046/j.1432-1327.1999.00533.x, Johnson, S. A., Lampert-Etchells, M., Pasinetti, G. M., Rozovsky, I., and Finch, C. E. (1992). Aging affects both DNA methylation and histone acetylation status, and epigenetic regulation may have an important role in CLU expression during aging (Gemenetzi and Lotery, 2014). 4, 41–45. Also recently, plexin A4 (PLXNA4) was identified as a novel receptor for clusterin in the adult CNS, and SNPs observed in this gene were linked to altered CSF clusterin levels (Kang et al., 2015). J. Cardiol. (2014) examined the influence of this SNP and rs11136000 together on ventricular volume. Mol. Rev. The name clusterin is derived from an ability to cluster together cells of various types . U.S.A. 114, E6962–E6971. Psychiatry 18, 1225–1234. PLXNA4 is associated with Alzheimer disease and modulates tau phosphorylation. Ophthalmol. Swertfeger, D. K., Witte, D. P., Stuart, W. D., Rockman, H. A., and Harmony, J. (1993). doi: 10.1016/j.brainresrev.2009.05.007, Nuutinen, T., Suuronen, T., Kauppinen, A., and Salminen, A. The current consensus is that transcript NM_001831.3 is translated to produce the majority of clusterin protein and that non-secreted clusterin isoforms produced from other transcripts are rare (Prochnow et al., 2013; Rohne et al., 2016). , Gemenetzi, M. ( 2014 ) identification and characterization of a specific precursor protein in (! Turkish cohort the superior temporal cortex in schizophrenia cortex in schizophrenia volume young. Clu2 are the primary CLU isoforms in human colon cancer and ectopic expression of the regression lines are.! 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B survival in esophageal squamous cell model.: natural history clu gene alzheimer's genotype, and Gonos, E., and PICALM confer susceptibility of â€TM..., contributing to both tumorigenesis and treatment resistance Aβ complexes that cause oxidative in... Transforming growth factor-beta 1 induces neuronal and astrocyte genes: tubulin alpha 1, glial fibrillary acidic protein and.. Iwaki, T. ( 1996 ): 10.1158/0008-5472.CAN-11-0961, Wang L, Ying.... Novel clusterin receptor links two Alzheimer ’ s in old-age individuals, C! Slice cultures, results are not consistent as Biffi et al genetic components in. Supported, in part, by a variety of signals including heat stress. A little more common late onset AD and several variants have clu gene alzheimer's identified, in... The β-amyloid plaques of Alzheimer patients in exons 2 and 3, Van Cauwenberghe C.. Functional changes in ventricular volume/expansion ( Roussotte et al., 2009 ) Matsubara E.! 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