Clusterin Deficiency in Eyes with Pseudoexfoliation Syndrome May Be Implicated in the Aggregation and Deposition of Pseudoexfoliative Material

Zenkel, Matthias; Kruse, Friedrich E.; Jünemann, Anselm; Naumann, Gottfried O.H.; Schlötzer‐Schrehardt, Ursula

doi:10.1167/iovs.05-1580

Cited by 96 publications

(85 citation statements)

References 47 publications

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“…Age related macular degeneration Drusen components Extracellular Clus (Sakaguchi et al, 2002), SAP (Ambati et al, 2003) Gelatinous drop-like corneal dystrophy Keratoepithelin Extracellular Clus (Nishida et al, 1999), SAP (Stix et al, 2005) Lattice type I corneal dystrophy M1S1 Extracellular Clus (Nishida et al, 1999), SAP (Stix et al, 2005) Pseudoexfoliation (PEX) syndrome PEX components Extracellular Clus (Zenkel et al, 2006), SAP (Schlotzer-Schrehardt et al, 1992) Down's syndrome Aβ Extracellular Clus (Kida et al, 1995), SAP (Kalaria and Grahovac 1990) Figure 1. A schematic representation of some of the fates that await polypeptide chains in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…In humans with AD (Duguid et al, 1989;May et al, 1989) and Creutzfeldt Jacob disease (Duguid et al, 1989;) the levels of clusterin mRNA are increased, however, there is no associated increase in clusterin protein levels in AD CSF (Lidstrom et al, 2001) and the level of clusterin protein in CSF is decreased by 2.5 fold in Creutzfeldt Jacob disease (Piubelli et al, 2006). In addition, decreased levels of clusterin in the eye are thought to be responsible for deposition of Pseudo exfoliation (PEX) material in PEX syndrome (Zenkel et al, 2006) (again clusterin is found associated with PEX deposits).…”

Section: When Quality Control Is Compromised?mentioning

confidence: 99%

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Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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Section: Discussionmentioning

confidence: 99%

Section: When Quality Control Is Compromised?mentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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“…cDNA synthesis and quantitative real-time PCR, using the MyiQ Thermal Cycler and software (Bio-Rad, Munich, Germany), was performed as previously described. 34 In brief, real-time PCR reactions (25 ml) contained 2 ml of the 1:5 diluted first-strand cDNA, 0.4 mM each of upstream and downstream primers, 3.5 mM MgCl 2 (CNTNAP2) or 3.0 mM MgCl 2 (b-actin) and IQ SYBR Green Supermix (Bio-Rad). All samples were analyzed in duplicates.…”

Section: Cntnap2 Expression Analysesmentioning

confidence: 99%

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

et al. 2010

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Genetic and nongenetic factors contribute to development of pseudoexfoliation (PEX) syndrome, a complex, age-related, generalized matrix process frequently associated with glaucoma. To identify specific genetic variants underlying its etiology, we performed a genome-wide association study (GWAS) using a DNA-pooling approach. Therefore, equimolar amounts of DNA samples of 80 subjects with PEX syndrome, 80 with PEX glaucoma (PEXG) and 80 controls were combined into separate pools and hybridized to 500K SNP arrays (Affymetrix). Array probe intensity data were analyzed and visualized with expressly developed software tools GPFrontend and GPGraphics in combination with GenePool software. For replication, independent German cohorts of 610 unrelated patients with PEX/PEXG and 364 controls as well as Italian cohorts of 249 patients and 190 controls were used. Of 19, 17 SNPs showing significant allele frequency difference in DNA pools were confirmed by individual genotyping. Further single genotyping at CNTNAP2 locus revealed association between PEX/PEXG for two SNPs, which was confirmed in an independent German but not the Italian cohort. Both SNPs remained significant in the combined German cohorts even after Bonferroni correction (rs2107856: P c ¼0.0108, rs2141388: P c ¼0.0072). CNTNAP2 was found to be ubiquitously expressed in all human ocular tissues, particularly in retina, and localized to cell membranes of epithelial, endothelial, smooth muscle, glial and neuronal cells. Confirming efficiency of GWAS with DNA-pooling approach by detection of the known LOXL1 locus, our study data show evidence for association of CNTNAP2 with PEX syndrome and PEXG in German patients.

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“…An overexpression of the basic fibroblast growth factor (bFGF), a disbalance of matrix metalloproteinases (MMPs)/tissue inhibitor of MMPs (TIMPs), and increased cellular and oxidative stress, describe a part of the pathological process that is characterized by an elastic microfibrillopathy. [5][6][7][8][9] Although there is no clear-cut evidence that the deposits would cause degeneration of the extraocular tissues, they have been associated with transient ischaemic attacks, 10 Alzheimer's disease, 11 asymptomatic myocardial dysfunction, 12 sensorineural hearing loss, 13 stroke, myocardial infarction, systemic hypertension, 14 and aneurysm of the abdominal aorta. 15 The purpose of this study was to investigate the prevalence of PEX syndrome in a Greek cataract population and its relation to glaucoma and coronary artery disease (CAD).…”

Section: Introductionmentioning

confidence: 99%

Pseudoexfoliation syndrome prevalence in Greek patients with cataract and its association to glaucoma and coronary artery disease

Ανδρικόπουλος

Mela

Georgakopoulos

et al. 2007

Eye

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Purpose To investigate the prevalence of glaucoma and coronary artery disease (CAD) in patients with cataract and pseudoexfoliation (PEX) syndrome. Methods Cross-sectional study of 2140 consecutive patients with cataract admitted at the University Hospital of Patras, Greece, for cataract surgery. Only patients with senile cataract were included in this study. All patients underwent a complete ophthalmological examination that included slit-lamp evaluation with dilated pupil for PEX material in the anterior segment, intraocular pressure (IOP) measurements, and optic disc cup examination. They also underwent an evaluation for CAD by a cardiologist. CAD was considered present if a patient had a history of myocardial infarction, or ischaemia, or abnormal coronary angiography. The patients were classified into two groups: the PEX and the non-PEX group. Results One thousand and eighty-eight (50.8%) patients were men and 1052 (49.2%) were women. The overall prevalence of PEX syndrome was found to be 27.9% and it was found to increase with progressing age. Bilateral PEX was more frequent than unilateral PEX, with the percentage of bilateral PEX raising with progressing age. A total of 132 patients (22.1%) in the PEX group exhibited glaucoma, while in the non-PEX group only 2.5% suffered glaucoma. PEX was also found to be positively associated with the risk for CAD among subjects 50 years or older.No association between CAD and glaucoma was found. Conclusions PEX syndrome constitutes a major glaucoma risk factor and a CAD risk factor. Patients with PEX should be informed and examined frequently as the risk is present throughout.

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Clusterin Deficiency in Eyes with Pseudoexfoliation Syndrome May Be Implicated in the Aggregation and Deposition of Pseudoexfoliative Material

Abstract: Considering the known role of clusterin as a highly efficient extracellular chaperone, its deficiency in the anterior segment of PEX eyes may promote the stress-induced aggregation and stable deposition of the pathologic extracellular matrix product characteristic of PEX syndrome.

Cited by 96 publications

References 47 publications

Extracellular Chaperones and Amyloids

Extracellular Chaperones and Amyloids

Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome

Pseudoexfoliation syndrome prevalence in Greek patients with cataract and its association to glaucoma and coronary artery disease

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