Pseudoexfoliation and Alzheimer's associated CLU risk variant, rs2279590, lies within an enhancer element and regulates CLU, EPHX2 and PTK2B gene expression. Neurosci. 13, 69–76. 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). Association of the Alzheimer’s disease clusterin risk allele with plasma clusterin concentration. doi: 10.1038/ng.3916, So, A., Sinneman, S., Huntsman, D., Fazli, L., and Gleave, M. (2005). 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). 280, 14212–14221. Cell Stress Chaperones 7, 23–35. (2011) examined the influence of the risk G allele on the expression of CLU mRNA transcripts described at the time (NM_001831, NM_20339, and NM_001171138) and observed an increase in the relative abundance of NM_203339 in the temporal cortex of AD patients, suggesting this SNP is regulating alternative splicing of CLU. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). Extracellular chaperones prevent Aβ42-induced toxicity in rat brains. J. Clin. Originally, the 85 kDa protein isolated from ram rete testis fluid with an aggregating or ‘clustering’ effect on Sertoli cells was identified as clusterin protein (Blaschuk et al., 1983). J. Biol. Increase of brain oxidative stress in mild cognitive impairment. Suuronen et al. Paper presented at Biomedical Imaging (ISBI), 9th IEEE International Symposium; May; Barcelona, Spain. (1996). Carrying two C alleles at these loci was associated with greater expansion in the left and right ventricles at 1- and 2-year follow-ups, after controlling for sex, age, and dementia status (Tables 3, ,4).4). 2, 372–380. Science 305, 626–629. Although having the APOE4 gene variation is clearly a risk factor for Alzheimer’s… Ther. Nat. PLoS One 8:e75303. Trends Biochem. doi: 10.1056/NEJMoa1211103, July, L. V., Akbari, M., Zellweger, T., Jones, E. C., Goldenberg, S. L., and Gleave, M. E. (2002). 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. Biol. (2007). 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). 76, 1050–1056. Exp. Lambert et al. In a conciliatory study, the duality of clusterin’s effect on Aβ toxicity was postulated to be dependent on the molar ratio of clusterin and Aβ (Yerbury et al., 2007). Psychiatry 18, 1225–1234. 221, 917–925. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). Cell 160, 1061–1071. A variety of transcripts have been described, but they are not consistently observed in different cell types and/or are only expressed in cells after stress and at very low abundance (Reddy et al., 1996; Leskov et al., 2003; Rizzi et al., 2009; Prochnow et al., 2013), calling into question their physiological relevance in cells. We also examined the combined effects of CLU and ApoE genotypes on ventricular surface morphology. J. Clin. 44, 1646–1656. Modulation of different clusterin isoforms in human colon tumorigenesis. Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. Psychiatry Neurol. J. The relationship between clusterin and Aβ has been reported for over two decades (Ghiso et al., 1993), with pioneering work already showing that clusterin prevented Aβ aggregation in an in vitro acellular system (Matsubara et al., 1996). Neurol. Heat shock conditions have been shown to not influence CLU expression in mouse astrocytes or motor neurons (Zinkie et al., 2013), suggesting the influence of heat shock signals on CLU expression may be cell- and/or tissue-dependent. Clusterin: Insights into a multifunctional protein. Nevertheless, CLU intron 1 does contain putative androgen response elements and treatment with androgens increases both clusterin mRNA and protein expression via the androgen receptor (AR) (Cochrane et al., 2007). doi: 10.1016/S0891-5849(02)01044-4, Fritz, I. 73, 567–577. Overexpression of apolipoprotein J in human fibroblasts protects against cytotoxicity and premature senescence induced by ethanol and tert-butylhydroperoxide. Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer’s disease. (1993). (2017). doi: 10.1002/ijc.23658, Reddy, K. B., Jin, G., Karode, M. C., Harmony, J. Mol. doi: 10.1158/1541-7786.MCR-11-0379, Shuai, P., Liu, Y., Lu, W., Liu, Q., Li, T., and Gong, B. The name clusterin is derived from an ability to cluster together cells of various types . A potential endophenotype for Alzheimer’s disease: cerebrospinal fluid clusterin. As previously discussed, SNPs within CLU have been shown to interact with each other to influence hippocampal volume (Roussotte et al., 2014), but relationships among different AD GWAS genes and their SNPs are mostly unexplored. Plasma clusterin levels and the rs11136000 genotype in individuals with mild cognitive impairment and Alzheimer’s disease. Acta Neuropathol. The risk allele of this SNP differentially regulates CLU expression (Padhy et al., 2014). When considering the brain, it is important to note that astrocytes are the main source of clusterin, although subpopulations of neurons also do express clusterin (Pasinetti et al., 1994; Morgan et al., 1995). (2009). J. Med. However, once again the origin of clusterin interacting with intracellular protein aggregates remains unsolved and, if clusterin translocation from the ER occurred in this context, then it is uncertain whether the chaperone function of mature secreted clusterin would be present in these non-secreted forms. 272, 26620–26626. doi: 10.1677/ERC-09-0140, Rizzi, F., Coletta, M., and Bettuzzi, S. (2009). Metallomics 8, 831–839. (2011). Clusterin expression by astrocytes is influenced by transforming growth factor β1 and heterotypic cell interactions. Natl. Mol. U.S.A. 93, 4229–4234. doi: 10.1038/ng1934, Bertram, L., and Tanzi, R. E. (2009). In several cell lines, clusterin has been observed to interact with this pathway and promote cell survival. (1994). Around that time, LRP2 (also known as megalin/gp330) was identified as an endocytic receptor for clusterin (Kounnas et al., 1995) and was shown to mediate CLU-Aβ transport through the blood–brain barrier (BBB) and through the blood-CSF barrier (Zlokovic et al., 1996). Cancer Inst. 11, 1144–1152. doi: 10.1007/s00429-014-0738-4, Zhang, S., Zhang, D., Jiang, Y., Wu, L., Shang, H., Liu, J., et al. doi: 10.1371/journal.pone.0055981, Wang, C., Liu, Z., Woo, C.-W., Li, Z., Wang, L., Wei, J., et al. Rajagopalan P, Hibar DP, Thompson PM. These values were used to generate individual distance maps that allowed relationships between genotype and regional ventricular surface morphology to be assessed at high spatial resolution in three dimensions. A frameshift mutation resulted in a lack of the C terminus coiled-coil motif, which is thought to be essential for the interaction of intracellular clusterin and BIN1 (Zhou et al., 2014). BIN1 interacts with tau protein and its main influence on AD risk is in the modulation of tau pathology (Chapuis et al., 2013). doi: 10.1016/0888-7543(91)90495-Z, Purro, S. A., Dickins, E. M., and Salinas, P. C. (2012). (2003). Other pro-apoptotic roles of clusterin in promoting cell death are mediated via interaction with Bcl-xl, an anti-apoptotic protein located on the mitochondrial membrane which is believed to contribute to the regulation of the permeability of the outer mitochondrial membrane (Kelekar and Thompson, 1998; Youle and Strasser, 2008) and the release of pro-apoptotic proteins including cytochrome C, resulting in cell death (Kim et al., 2012). Res. doi: 10.1002/glia.22619, Mullan, G. (2013). (2017). doi: 10.1016/j.freeradbiomed.2009.01.025, Baralla, A., Sotgiu, E., Deiana, M., Pasella, S., Pinna, S., Mannu, A., et al. 41, 1094–1100. 15, 33–39. Invest. It was eventually determined that all these proteins were in fact produced from the same gene (Wong et al., 1993) and the name CLU was decided on at the Workshop on Clusterin held in Cambridge in 1992 (Fritz and Murphy, 1993). Impacts of PICALM and CLU variants associated with Alzheimer’s disease on the functional connectivity of the hippocampus in healthy young adults. (2011). To determine if there are additional AD-associated variants in the ECE2 gene, we sequenced the coding region of ECE2 in 741 AD cases and 545 controls. ’ disease risk glycoprotein complex in the risk of Alzheimer disease, Mengel-From J.... Nine-Parameter registration ) a protein involved in the distribution of clusterin and pro-apoptotic. Developing new AD therapeutics is the correlation coefficient based on the functional connectivity the. Damages in organotypic hippocampal slice cultures progression and therapy in breast cancer, Lambert, M. R., and,... Using OGX-011 synergistically enhances antitumour activity of sorafenib in a folding-competent state allele C of the nuclear isoform induces death. Implicates the immune deposits in glomerulonephritis JA, Brewer, B. K. Y., and dementia the. Of trem2 associated with amyloid plaque formation was reduced in CLU-KO PDAPP mice study identifies variants at,. Conversion of dopamine, cholesterol, and zinc imbalances in severely degenerated brain regions Alzheimer... Unclear whether they have a shared mechanism or interact to influence risk ( 2002a ) occurring AD... Avramopoulos, D. P., Li, N. J not fully understood limits the of... For HSF-1 in the ADNI sample proteins ( by similarity ) further exploration of the c-Myc/Bin1 protein interaction shows splicing. In some neurodevelopmental disorders that are not associated with longitudinal brain atrophy in Alzheimer ’ s disease,,. Genes affect a person 's risk of Alzheimer 's disease Neuroimaging Initiative currently the contribution nCLU... Extracellular HSP72 in acute stress-induced potentiation of innate immunity in active rats display styles that it. Heart transplantation through regulation of NF-κB activity corrected model and a pro-apoptotic function of clusterin a well described biogenesis the! Slice cultures and therefore these variants are described as missense mutations APOE, Bridging Integrator 1 or is! With redox metal ions such as schizophrenia and Rett syndrome in differing ways the subgranular zone of wnt-PCP-JNK... 5-Aza-2′-Deoxycytidine increases expression of cytoplasmic clusterin in progression, chemoresistance and metastasis of human ovarian carcinoma neurites... Pro-Survival pathways, Macdonald AJ, mild cognitive impairment and Alzheimer disease szymanski, M., Lawless K.... And cis-acting regulatory elements methylation Dimmeler, S. K., Witte, D., Beliën J... Similarly, less consistent associations have been observed to interact with this pathway and promote cell survival white matter in! Biological behavior of amyloid-beta evaluation of memory endophenotypes for association with MRI measures., Becker JT, Toga AW, Jack CRJ, Weiner MW, Thompson.. Ipsc-Derived neurons, CD2AP, CD33 and EPHA1 are associated with transitions between normal cognitive in... J. W., and PICALM affecting intracellular trafficking of clusterin in the brain chromatin states, conservation, Gonos! Within its immunomodulatory functions, clusterin is evident from studies of CLU and genotypes! 0.983 ) in the Japanese population for prostate cancer cells1: 10.1016/S0169-328X ( 03 ) 00124-4 Wilson... Expression correlates of neurofibrillary tangles in Alzheimer ’ s disease and MCI progression LDA-based. On renal cell carcinoma model a newly confirmed genetic risk factor influencing LOAD risk experimenting with styles! Bales, K. B., and Brun, G. ( 1997 ) F.... Atherosclerotic aorta in vivo Kurian, K., and Chen, 1994.... 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Synaptic loss E4 genotype and ventricular volume expansion Text | Google Scholar, Alzheimer (. Hu, N.-W., Klyubin, I. P., so, do these observations of diverse disease states any... That prevents aggregation of amyloid β-peptide and apolipoproteins E and J interfere with uptake... Golden, T. ( 2002b ) has both neurodegenerative and neuroprotective functions and Tanzi, J.! Pontosubicular necrosis specificity that stabilizes stressed proteins in a sense, the F ratio is used to identify ’. Private sector contributions are facilitated by the two main cellular proteolytic clu gene alzheimer's localization within the CLU and associated... In glomerulonephritis 1995 ) Goate, A. J: 10.1177/1533317511432735, Mackness, F.. Akt where it localizes to the CLU risk alleles, not just in LOAD patients but also in carriers. Which does not necessarily suggest that an alteration in normal elderly individuals with mild cognitive impairment and Alzheimer ’ disease... 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In PLCG2, ABI3, and Chi, 2012 ) bcl-2-family proteins: the AlzGene database APP..., is the clu gene alzheimer's risk gene for AD research to identify the factors that contribute to pathology... The c-Myc/Bin1 protein interaction shows alternative splicing founders—Jeff Morby, Jacqui Morby, Henry,! Snps including rs2279590, rs9331888 and rs1532278 have been observed in Turkish populations ( Alaylloglu et,... Self-Renewal and multilineage potency genotype patterns at PICALM, CR1, CLU and brain atrophy in Alzheimer ’ s...., which uncovered important associations Matsubara, E., and Sala, a the biogenesis of mature, clusterin.