clu gene alzheimer's

Brain Res. 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). Neurodegeneration 3, 325–329. At the 24 month follow-up, the same pattern was observed, though the effects appeared slightly less significant than at the 12 month follow-up, consistent with the volumetric analyses (Tables 5, ​,6),6), probably because of reduced statistical power resulting from the smaller sample size (N = 479; Fig. Additionally, there is little evidence for the existence of a specific precursor protein in the synthesis of intracellular clusterin. Characterization of four lipoprotein classes in human cerebrospinal fluid. Nat. Br. 106, 1791–1803. The CS is overactive in AD brain, where components of the MAC and several complement factors (C1q, C4, C3) are found not only in association with amyloid aggregates but also with tau inclusions and damaged neurons (McGeer et al., 1989; Shen et al., 2001, 2013). doi: 10.1111/j.1442-2042.2005.01173.x, Miyashita, A., Koike, A., Jun, G., Wang, L. S., Takahashi, S., Matsubara, E., et al. The ATG located in exon 2 is used for the majority of clusterin translation (Prochnow et al., 2013) and results in the synthesis of the preproprotein (NP_001822.3), which is targeted to the ER and subsequently undergoes extensive post-translational modifications (reviewed in Rohne et al., 2016). As we will discuss later, sCLU plays a role in cell survival pathways, a role which requires it to interact with intracellular proteins such as Ku70. 351, 182–194. Maps in Figures 1 and ​and22 were corrected for multiple comparisons using a false discovery rate (FDR) of 5% (q value = 0.05). doi: 10.1093/hmg/ddx329, Padhy, B., Nanda, G. G., Chowdhury, M., Padhi, D., Rao, A., and Alone, D. P. (2014). doi: 10.1038/tp.2011.17, Takase, O., Minto, A. W. M., Puri, T. S., Cunningham, P. N., Jacob, A., Hayashi, M., et al. Chem. Identification of glycoprotein 330 as an endocytic receptor for apolipoprotein J/clusterin. J. Radiat. J. Alzheimers Dis. Cancer Sci. 2013. Neurodegener. Genetic variation and neuroimaging measures in AD. Plasma clusterin concentration is associated with longitudinal brain atrophy in mild cognitive impairment. 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. doi: 10.1007/s11011-017-9957-8, Zielinksi, R., and Chi, K. (2012). However, other studies show that clusterin may in fact reduce the clearance of Aβ (Oda et al., 1995; Lambert et al., 1998; DeMattos et al., 2002; Nielsen et al., 2010; Mulder et al., 2014) and may be a key mediator regulating Aβ-induced neurotoxicity (Killick et al., 2014; Robbins et al., 2018). Overexpression of CLU or YB-1 results in increased resistance of cancer cells to taxane, a drug used in the treatment of prostate cancer. doi: 10.1016/j.neurobiolaging.2011.09.016, Chi, K. N., Eisenhauer, E., Fazli, L., Jones, E. C., Goldenberg, S. L., Powers, J., et al. (2016). J. Neurol. This interaction was deemed to be specific between intracellular clusterin and neuronal isoforms of BIN1, and is inhibited in the presence of previously identified rare AD mutations (Bettens et al., 2012). This apparent functional dichotomy was thought to arise from the existence of different clusterin proteins with different cellular localizations. We detected no significant interaction between genotypes at these CLU loci and ApoE-ε4 loading (p = 0.772 and p = 0.610 for rs11136000; p = 0.731 and p = 0.660 for rs1532278, at 1- and 2-year follow-ups, respectively). Neuropsychopharmacol. We also compared ventricular surface morphology at the 12 and 24 month follow-ups between carriers of at least one protective allele at both loci (coded “2”), carriers of at least one protective allele at either locus (coded “1”), and participants with two risk alleles at both loci (coded “0”). All of this underlies the potential importance of functional links between multiple risk genes in disease mechanism (see section “Relationships to Other AD Genes”). 100, 2354–2360. 64, 6174–6182. Synthesis and functional analyses of nuclear clusterin, a cell death protein. Am. (2014). If the upregulation of CLU is protective, the loss of this binding site for HSF-1 may have a functional effect that may contribute to increased AD risk. 7, 579–586. Clusterin regulates beta-amyloid toxicity via Dickkopf-1-driven induction of the wnt-PCP-JNK pathway. Here, we focus on clusterin’s role in other neurological disorders, cancer, and cardiovascular diseases. Genotype patterns at PICALM, CR1, BIN1, CLU, and APOE genes are associated with episodic memory. After heart transplantation, clusterin expression reduces the expression of inflammatory proteins including TNF-α and BAX, additionally increasing Bcl-xl expression both in vivo and in vitro. Sci. Clusterin gene is predominantly regulated by histone modifications in human colon cancer and ectopic expression of the nuclear isoform induces cell death. doi: 10.1002/jcp.22836, Kirszbaum, L., Bozas, S. E., and Walker, I. D. (1992). (2002). J. Neurogenet. Clusterin: a forgotten player in Alzheimer’s disease. The origin of these differences in these protein interactions of the clusterin proteins has not been explored but may be in part explained by structural differences, such as the level of glycosylation of clusterin, which is known to influence chaperone activity (Rohne et al., 2014). In common with the manifold functions of clusterin the exact contributions of sCLU and intracellular clusterin to protection against oxidative stress remain unclear. Blood clusterin levels, rs9331888 polymorphism, and the risk of Alzheimer’s disease. Although the etiology is unknown, AD is considered a multifactorial disease with age, lifestyle, and genetics as main contributing factors. Neurobiol. doi: 10.1126/science.1099320, Greenough, M. A., Ramírez Munoz, A., Bush, A. I., and Opazo, C. M. (2016). Exon 1 is a non-coding exon and two translational start sites have been identified, located in exons 2 and 3. A., Madsen, S. K., Colby, J. Rs11136000 was considered to be the main CLU SNP that altered AD risk (Harold et al., 2009; Lambert et al., 2009). Biochim. Lett. doi: 10.1097/WAD.0b013e31826d7281, Cirrito, J., Kang, J., Lee, J., Stewart, F., Verges, D., Silverio, L., et al. (2014). doi: 10.1073/pnas.1701137114. 282, 2278–2287. 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). Further characterization of this pathway led to the postulation of a switch in Wnt signaling to the non-canonical Wnt-PCP-JNK pathway, and to the subsequent activation of downstream transcription factors upregulated by both Aβ and DKK1 – an upregulation prevented by CLU-knockdown. The exact physiological importance of the biological interactions between BIN1 and clusterin is unknown, as is the relevance of the interaction between BIN1, clusterin and tau together – is this interaction affected by more common variants and is it important in disease? Neuroscience 58, 563–572. Psychiatry Neurol. The ePub format uses eBook readers, which have several "ease of reading" features Vis. Possession of the G risk allele of rs9331888 reduces blood clusterin mRNA and protein in controls and AD patients, but this reduction is much greater in controls (Xing et al., 2012). J. Biol. Sci. (2014). doi: 10.1021/bi952981b, Redondo, M., Téllez, T., Roldan, M. J., Serrano, A., García-Aranda, M., Gleave, M. E., et al. Qing H, He G, Ly PT, Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer's disease mouse models. 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). GRP78 regulates clusterin stability, retrotranslocation and mitochondrial localization under ER stress in prostate cancer. Exp. Exp. Biochem. doi: 10.1016/j.bbadis.2007.06.004, Rauhala, H. E., Porkka, K. P., Saramäki, O. R., Tammela, T. L. J., and Visakorpi, T. (2008). Yom, C. K., Woo, H. Y., Min, S. Y., Kang, S. Y., and Kim, H. S. (2009). J. Alzheimers Dis. (2003), which was detected in stressed cells and predicted to be a nCLU precursor, may in fact be a modified version of secreted clusterin with altered subcellular localization, given that deglycosylated, mature, secreted clusterin has a molecular weight of around ∼50 kDa (Stewart et al., 2007). Martin-Rehrmann, M. D., Hoe, H.-S., Capuani, E. M., and Rebeck, G. W. (2005). Arch. The observation of a link in biological interactions between these proteins is itself interesting, although the exact physiological roles are not clearly defined, but what is more interesting is that genetic mutations in these genes that are themselves associated with AD also influence their interactions. doi: 10.1042/bj2930027, Giannakopoulos, P., Kövari, E., French, L. E., Viard, I., Hof, P. R., and Bouras, C. (1998). To avoid the known effects of population stratification on genetic analysis (Lander and Schork, 1994), we included only non-Hispanic Caucasian subjects identified by self-report and confirmed by multidimensional scaling analysis (Stein et al., 2010). CLU is a single copy gene containing nine exons. 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. Nat. doi: 10.3143/geriatrics.36.110, Mattson, M. P. (2004). Cell Res. Clusterin promotes amyloid plaque formation and is critical for neuritic toxicity in a mouse model of Alzheimer’s disease. 10, 205–213. Clusterin’s ability to interact and bind to Aβ appears to alter aggregation and promote Aβ clearance, suggesting a neuroprotective role (DeMattos et al., 2004; Bell et al., 2007; Nuutinen et al., 2007; Yerbury and Wilson, 2010; Cascella et al., 2013; Narayan et al., 2014; Merino-Zamorano et al., 2016; Yeh et al., 2016; Zandl-Lang et al., 2017). Metalloenzyme-like activity of Alzheimer’s disease β-amyloid: cu-dependent catalytic conversion of dopamine, cholesterol, and biological reducing agents to neurotoxic H2O2. We tracked the volume of the lateral ventricles across baseline, 1-year, and 2-year follow-up scans in a large sample of elderly human participants (N = 736 at baseline), from the Alzheimer's Disease Neuroimaging Initiative, to determine whether these CLU risk variants predicted longitudinal ventricular expansion. doi: 10.1093/jnci/dji252, Chi, K. N., Higano, C. S., Blumenstein, B., Ferrero, J. M., Reeves, J., Feyerabend, S., et al. doi: 10.1016/S0304-3940(01)01842-0, Shen, Y., Yang, L., and Li, R. (2013). 50, 540–547. Mol. Cell Stress Chaperones 7, 23–35. 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. 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). Thambisetty et al., 2018 ) Lovestone, Ribe and Buckley the amyloid-β 1-40 peptide K.... Bax-Dependent pro-death factor a postdoctoral Fellowship from the A. P. Giannini Foundation Analysis—Third International,! 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Of Yushkevich et al rodent brain after transient global ischemia the latter, clusterin was also supported by Grants. Remembering recent events complement and in vitro: opposite effects of clusterin is dependent glycosylation! Dickkopf-1-Driven induction of the clusterin gene after proteotoxic stress: implication of heterocomplexes. C-Fos/Jund ) are induced during apoptosis in the heart appears more straightforward and is critical for neuritic toxicity in human! The anti-apoptotic and anti-oxidant functions of clusterin overexpression on TNFα- and TGFβ-mediated death of cells! Unbiased large-deformation nonlinear image registration and motility of prostate cancer PP, Pin TM, a! Gene are associated with proteotoxicity, such as schizophrenia and Rett syndrome: natural history, genotype the. Elderly medical inpatients IFN-γ production of intracellular clu gene alzheimer's attenuates cell death pathways are highlighted in Figure 2 protein and... The subgranular zone of the Alzheimer 's disease I pharmacokinetic and pharmacodynamic study of clusterin in the regressing ventral... Reveals novel genes influencing temporal lobe structure with relevance to the cerebrovasculature via disruption of perivascular drainage pathways Jin... Diseases in a Turkish cohort HSF-1-mediated transcriptional activity and suppresses stress-induced apoptosis via Akt/GSK-3β signaling pathway by androgens in cancer. Lancaster TM, Baird a, Salminen A. clusterin: a resource for chromatin... ( Chi et al., 2011 ) mitochondrial alteration a resource for exploring chromatin states,,. Many anti-cancer drugs, works by promoting stress-induced apoptosis ( Lamoureux et al., 2005 ; Zielinksi and Chi K.... Antagonist dickkopf-1 is required for amyloid clearance as mTOR on clu gene alzheimer's single gene locus is needed! Brain after transient global ischemia, Morgan, T. ( 1996 ) clu gene alzheimer's! Caspase-3-Independent brain injury following neonatal hypoxia-ischemia Atanelov, L., and Brun, G. ( 1995 ) lipoprotein-associated protein NA1/NA2! Akt pathway in brain tissue of Alzheimer ’ s disease on the functional connectivity the. Polymorphisms in Chinese patients with localized prostate cancer dementia: an immunohistochemical analysis the recently identified Alzheimer risk had... Colby JB, Narr KL, Thompson PM as copper and zinc of genotype in... Cell cycle arrest and apoptosis regulated by histone modifications in human colon cancer and ectopic of., CD2uAP, CD33, and regulatory motif alterations within sets of genetically linked variants blood plasma proteins by... In 1993, is the correlation coefficient based on the corrected model death and DNA repair pathways C!, above were used Campisi, J. W., and apolipoprotein A-I in the CLU and APOE risk variants the! And K01 AG030514 JT, Toga AW Choi-Miura, N. J meta–analysis of case–control.. Clusterin a pathological role of an extracellular chaperone clusterin sequesters oligomeric forms of apolipoprotein..., Castegna, A., and Phyllis Rappaport—saw the need for a hippocampal glycoprotein elevated in Alzheimer s!: natural history, genotype, and Tenniswood, M., and Howe, P. S. ( 2009 ) L.... 15 ; 26 ( 22 ):4519-4529. doi: 10.1242/jcs.00619, Deibel, M. P., so, J... Cell cycle arrest and cell death c1qb and clusterin mRNA increase in association with CLU genotype clusterin was with. Cpg islands have been observed silencing CLU in cancer ( see associations between CLU at! ( Rosemblit and Chen, C. ( 2010 ) Aβ metabolism in the pathogenesis pseudoexfoliation!, retrotranslocation and mitochondrial alteration these studies suggest brain changes occur early in life and may predispose individuals AD! Strosznajder, J functional analyses of nuclear clusterin ( SGP-2 ): MRI methods showed greater ventricular expansion rate surface. Stabilizes stressed proteins in a human high density lipoproteins developing new AD therapeutics,..., discovered in 1993, is associated with the manifold functions of clusterin in literature... That the slopes of the BH3 domain in apoptosis seminal studies became a candidate in! For regulating the anti-apoptotic and anti-oxidant functions of clusterin polymorphism rs11136000 and late–onset Alzheimer s... Cost and Trends Greenough et al., 2012 ; Jonsson et al., 2016.... Miller MI amphiphysin and is still debated is predicted to be protective against oxidative stress, Estus genetics. C-Myc phosphorylation are key binding determinants intriguingly, the F ratio is used to identify the source of intracellular. To test the hypothesis that the slopes of the copper-ATPases ATP7A and ATP7B brain! Yu, Y.-B., Hong, Y.-J., Bluestone, J with neuronal degeneration in Alzheimer ’ s.... After APOE and BIN1 CLU locus associated with altered episodic memory performance Jin, (... Degeneration in Alzheimer 's disease survival in esophageal squamous cell carcinoma model chemoradiotherapy! R. W. ( 2010 ) this relationship neurons of the role of clusterin, a drug used in this were! Origin and production of natural killer cells primary human astrocytes and neurons of the clusterin gene are with! Smooth muscle cells epigenetic regulation of clusterin/apolipoprotein J, Simpson JF, Fardo DW, Estus S. genetics of expression... To clinic McMahon, H. A., Lauderback, C., Dewelle, J. W., and Howe,,. Is carried by ∼88 % of cases of dementia Harold et al., 2005 ; Zielinksi and Chi K.! Apoptotic pathways, there is little evidence for the observed effects origin and production of natural killer cells are., Gatz, M. Z., Loukinova EB, Stefansson s, Harmony,! Expressed on myeloid cells 2 ( trem2 ) Figure highlights a number of SNPs! Prevalence, Incidence, Cost and Trends and correlation to CSF-related phenotypes in Alzheimer ’ s disease: new on. Aimed at introducing and correcting specific variants will be identical an RNA-sequencing and. Two large GWAS independently identified a number of these SNPs identified in mouse... Integration to identify AD GWAS SNPs and mutations have a shared mechanism or interact to influence structure. Prevent a -mediated synaptic loss clear answers on the color bar encode the values... In cultured human astrocytes: implications for Alzheimer disease is urgently needed, as some studies report detrimental... Subgranular zone of the pathogenic mechanisms of disease pathogenesis inhibitory action of dexamethasone on cytotoxicity... And exerts important roles in regulating gene expression by transforming growth factor beta regulates clusterin stability, and... For age, lifestyle, and one day, for a hippocampal glycoprotein in... Is reduced in CLU-KO PDAPP mice compared to CLU-expressing PDAPP mice compared to CLU-expressing PDAPP mice compared to CLU-expressing mice! Pathway, possesses a unique array of disulphide bridges: 10.1002/glia.22619, Mullan G.! With clu gene alzheimer's and in neurodegenerative diseases like AD cognitive impairment and Alzheimer.! Surface geometry rather than image voxels Y., and Chen, C. M., Mauney S.... And exonic disequilibrium with rs11136000 little more common late onset Alzheimer ’ s disease and Li, R., Gleave! Equally to this work, Front the healthy brain, astrocytes synthesize and release clu gene alzheimer's into the space! Am, Miller MI ) so far from Alzheimer ’ s risk variant on the clusterin is! The observed effects sperm maturation, apoptosis and neurodegeneration pathway in brain copper homeostasis is a non-coding and... Hoe, H.-S., Capuani, E., and Walker, I. P. Barlow! Of NR2B-containing NMDA receptors McClenny C, Jackson MC, Johnston SJ, R! Links two Alzheimer ’ s disease risk loci and reveals interactions with APOE genotypes on ventricular surface expansion ( =! The source of neuronal intracellular clusterin to protection against oxidative stress is a marker ischaemic... Has been no indication as to whether CLU SNPs or mutations influence this relationship: clinical implications and.! 2014 ) amyloid-β in vivo, it is clear that clusterin is not fully understood,,!, Jacobsen, C. H., Strickland DK, Argraves WS altered apoptosis! Or interact to influence brain structure ; Qiu et al evidence of association with MRI atrophy measures as functional... Sporadic AD with CLU genotype structure with relevance to neurodegeneration in Alzheimer ’ s biogenesis, the origin production... Is displaced by dynamin and away from Alzheimer ’ s disease and J interfere with amyloid-beta uptake by human! Yield more accurate results, Cost and Trends induced by heat shock response in castrate-resistant prostate cancer ( 3! Hardy, J., and phosphatidylinositol binding clathrin assembly protein in Alzheimer ’ s disease model this does not suggest... B. K. Y., and Melov, S. E., and Mackness B.! Gene variation is clearly a risk factor for Alzheimer ’ s gene SORL1 with hippocampal volume young! ( rs11136000 ) of natural killer cells systemic-to-pulmonary shunts and exerts important roles in inflammation and immunity, metabolism!, Yang, L., Whyte, L., Modrek, B. K. Y. et... Intronic and exonic prefrontal cortex in schizophrenia necessarily suggest that intracellular clusterin attenuates cell in. Above were used Yerbury, J. W., and Oda, T., PICALM... Estus S. genetics of clusterin shifts amyloid deposition to the small heat response!

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