Clusterin increases post‐ischemic damages in organotypic hippocampal slice cultures

Hakkoum, David; Imhof, Anouk; Vallet, Philippe; Boze, Helène; Moulin, G.; Charnay, Yves; Stoppini, Luc; Aronow, Bruce J.; Bouras, Constantin; Giannakopoulos, Pantéleimon

doi:10.1111/j.1471-4159.2008.05519.x

Cited by 15 publications

(14 citation statements)

References 60 publications

(139 reference statements)

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“…Previous findings from animal studies suggested that Clusterin increases post-ischemic damage and may exert a negative effect on the structural integrity and functionality of hippocampal neurons. 44 Several limitations may be noted in this study. First, sample size (558 patients and 566 controls) might not be adequate.…”

Section: Discussionmentioning

confidence: 90%

Replication of a genome-wide association study of panic disorder in a Japanese population

Otowa

Tanii

Sugaya³

et al. 2009

J Hum Genet

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Panic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Although a number of association and linkage studies have been conducted, no gene has been identified as a susceptibility locus. We previously conducted a genome-wide association analysis of PD in 200 Japanese patients and the same number of controls, using a 500 K single nucleotide polymorphisms (SNPs) chip. In this study, we report a replication analysis of PD using the DigTag2 assay. The second stage sample consisted of 558 Japanese patients and 566 controls. Thirty-two markers were tested in a replication sample. As a result, no significant association was found after correction for multiple testing. However, the difference was observed at the nominal allele P-value o0.05 for two SNPs (rs6733840 and rs132617). We also conducted haplotype analyses of SNPs in the APOL3 and CLU genes. Our results failed to show any significant association with PD in these genes. Further studies on these variants with a larger sample size may be worth testing to confirm the results. Keywords: genome-wide association study (GWAS); Japanese population; panic disorder; replication; single nucleotide polymorphism (SNP) INTRODUCTIONPanic disorder (PD) is an anxiety disorder characterized by recurrent and unexpected panic attacks, subsequent worry and phobic avoidance. Life prevalence of PD is 1-3% and twice as many women as men suffer from the disorder. 1 The disorder frequently takes a chronic course, with many remissions and relapses. 2 Genetic epidemiological studies including family and twin studies have shown that genetic as well as environmental factors have an important role in the pathogeneses of PD. First-degree relatives of proband with PD have an approximately fivefold increased risk of PD. 3,4 Twin studies show that about 40% of the liability towards PD consists of heritable factors [5][6][7] However, the etiology of PD is currently unknown.

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Section: Discussionmentioning

confidence: 90%

Replication of a genome-wide association study of panic disorder in a Japanese population

Otowa

Tanii

Sugaya³

et al. 2009

J Hum Genet

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“…While extracellular Zn 2+ via the ZnR is shown to promote cell survival, an opposing role is suggested for intracellular Zn 2+ rise that often leads to cell death [59], [60], [61], [62], [63]. Interestingly, upregulation of the pro-apoptotic nCLU form by ischemia, which is known to induce a rise in intracellular Zn 2+ , has been shown to play a role in neuronal death [64], [65]. Consistent with such a role, intracellular Zn 2+ or Cd 2+ rise induces expression of the pro-apoptotic nCLU and triggers testicular germ cells death [66].…”

Section: Discussionmentioning

confidence: 99%

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

et al. 2012

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Zinc enhances epithelial proliferation, protects the digestive epithelial layer and has profound antiulcerative and antidiarrheal roles in the colon. Despite the clinical significance of this ion, the mechanisms linking zinc to these cellular processes are poorly understood. We have previously identified an extracellular Zn2+ sensing G-protein coupled receptor (ZnR) that activates Ca2+ signaling in colonocytes, but its molecular identity as well as its effects on colonocytes' survival remained elusive. Here, we show that Zn2+, by activation of the ZnR, protects HT29 colonocytes from butyrate induced cell death. Silencing of the G-protein coupled receptor GPR39 expression abolished ZnR-dependent Ca2+ release and Zn2+-dependent survival of butyrate-treated colonocytes. Importantly, GPR39 also mediated ZnR-dependent upregulation of Na+/H+ exchange activity as this activity was found in native colon tissue but not in tissue obtained from GPR39 knock-out mice. Although ZnR-dependent upregulation of Na+/H+ exchange reduced the cellular acid load induced by butyrate, it did not rescue HT29 cells from butyrate induced cell death. ZnR/GPR39 activation however, increased the expression of the anti-apoptotic protein clusterin in butyrate-treated cells. Furthermore, silencing of clusterin abolished the Zn2+-dependent survival of HT29 cells. Altogether, our results demonstrate that extracellular Zn2+, acting through ZnR, regulates intracellular pH and clusterin expression thereby enhancing survival of HT29 colonocytes. Moreover, we identify GPR39 as the molecular moiety of ZnR in HT29 and native colonocytes.

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“…It should be noted that the experimental conditions were different, as neonatal hypoxia/ischemia and permanent ischemia by middle cerebral artery occlusion in adult mice were used, respectively. CLU increases post-ischemic cell death in hippocampal slice cultures [42], implying a pro-apoptotic role for CLU.…”

Section: Clu In Brain Damage and Neurodegenerationmentioning

confidence: 99%

Proapoptotic role of nuclear clusterin in brain

Kim

Choi

2011

Anat Cell Biol

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Clusterin (CLU) is a multifunctional glycoprotein that has secretory and nuclear isoforms. The two isoforms are known to play opposite roles in cell survival/death. In this review, we summarize recent progress on the pro-apoptotic function of nuclear CLU in vitro and in vivo and discuss previous reports on the role of CLU in brain damage and neurodegeneration. ximately 50 kDa and detected as a ~60 kDa glycosylated precursor secretory CLU (psCLU). It is cleaved to α and β chains of ~40 kDa and further glycosylated to form mature disulfide-linked heterodimeric secretory CLU (sCLU, 75-80 kDa). The nCLU transcript lacks the endoplasmic reticulum (ER)-targeting sequences at exon 2 and utilizes the second ATG site at exon 3 (Fig. 1A). The product is detected as the ~49 kDa nonglycosylated precursor nCLU in the cytosol and as a ~55 kDa glycosylated protein (nCLU) in the nucleus [8]. The CLU protein has two coiled coil domains responsible for interacting with other proteins, e.g., Ku70, which binds to CLU upon DNA damage [9] and two nuclear localization signals [7].

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Clusterin increases post‐ischemic damages in organotypic hippocampal slice cultures

Cited by 15 publications

References 60 publications

Replication of a genome-wide association study of panic disorder in a Japanese population

Replication of a genome-wide association study of panic disorder in a Japanese population

Zinc Sensing Receptor Signaling, Mediated by GPR39, Reduces Butyrate-Induced Cell Death in HT29 Colonocytes via Upregulation of Clusterin

Proapoptotic role of nuclear clusterin in brain

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