Clusterin (CLU; also known as apolipoprotein J, ApoJ) is a protein of inconstant structure known to be involved in diverse processes inside and outside of brain cells. CLU can act as a protein chaperon or protein solubilizer, lipid transporter as well as redox sensor and be anti- or proapoptotic, depending on context. Primary structure of CLU is encoded by CLU gene which contains single nucleotide polymorphisms (SNP's) associated with the risk of late-onset Alzheimer's disease (LOAD). Studying a sample of Czech population and using the case-control association approach we identified C allele of the SNP rs11136000 as conferring a reduced risk of LOAD, more so in females than in males. Additionally, data from two smaller subsets of the population sample suggested a possible association of rs11136000 with diabetes mellitus. In a parallel study, we found no association between rs11136000 and mild cognitive impairment (MCI). Our findings on rs11136000 and LOAD contradict those of some previous studies done elsewhere. We discuss the multiple roles of CLU in a broad range of molecular mechanisms that may contribute to the variability of genetic studies of CLU in various ethnic groups. The above discordance notwithstanding, our conclusions support the association of rs1113600 with the risk of LOAD.

• Keywords
• Clusterin, Genetic risk, Late-onset Alzheimer’s disease, Mild cognitive impairment, Neurodegeneration, Neuroprotection, Single nucleotide polymorphism,
• MeSH
• Alzheimer Disease etiology   genetics   MeSH
• Genetic Predisposition to Disease MeSH
• Polymorphism, Single Nucleotide MeSH
• Clusterin genetics   MeSH
• Cognitive Dysfunction etiology   genetics   MeSH
• Humans MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• CLU protein, human MeSH Browser
• Clusterin MeSH

BACKGROUND: Cholinergic hypothesis of Alzheimer's disease (AD) is based on the findings that a reduced and/or perturbed cholinergic activity in the central nervous system correlates with cognitive decline in patients with Alzheimer's disease. The hypothesis resulted in the development of centrally-acting agents potentiating cholinergic neurotransmission; these drugs, however, only slowed down the cognitive decline and could not prevent it. Consequently, the perturbation of the central cholinergic signalling has been accepted as a part of the Alzheimer's aetiology but not necessarily the primary cause of the disease. In the present study we have focused on the rs3810950 polymorphism of ChAT (choline acetyltransferase) gene that has not been studied in Czech population before. METHODS: We carried out an association study to test for a relationship between the rs3810950 polymorphism and Alzheimer's disease in a group of 1186 persons; 759 patients with Alzheimer's disease and 427 control subjects. Furthermore, we performed molecular modelling of the terminal domain (1st-126th amino acid residue) of one of the ChAT isoforms (M) to visualise in silico whether the rs3810950 polymorphism (A120T) can change any features of the tertiary structure of the protein which would have a potential to alter its function. RESULTS: The AA genotype of CHAT was associated with a 1.25 times higher risk of AD (p < 0.002) thus demonstrating that the rs3810950 polymorphism can have a modest but statistically significant effect on the risk of AD in the Czech population. Furthermore, the molecular modelling indicated that the polymorphism is likely to be associated with significant variations in the tertiary structure of the protein molecule which may impact its enzyme activity. CONCLUSIONS: Our findings are consistent with the results of the meta-analytical studies of the relationship between rs3810950 polymorphism and AD and provide further material evidence for a direct (primary) involvement of cholinergic mechanisms in the etiopathogenesis of AD, particularly as a factor in cognitive decline and perturbed conscious awareness commonly observed in patients with AD.

• Keywords
• Alzheimer’s disease, Association, Choline acetyltransferase, Gene, Polymorphism,
• MeSH
• Alzheimer Disease genetics   MeSH
• Choline O-Acetyltransferase genetics   metabolism   MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide * MeSH
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH
• Names of Substances
• Choline O-Acetyltransferase MeSH

BACKGROUND: The objective of the study was to examine several polymorphisms in DISC1 and CTNX3 genes as possible risk factors in schizophrenia. DISC1 (disrupted-in-schizophrenia 1) has been studied extensively in relation to mental disease while CTXN3, has only recently emerged as a potential "candidate" gene in schizophrenia. CTXN3 resides in a genomic region (5q21-34) known to be associated with schizophrenia and encodes a protein cortexin 3 which is highly enriched in brain. METHODS: We used ethnically homogeneous samples of 175 male patients and 184 male control subjects. All patients were interviewed by two similarly qualified psychiatrists. Controls were interviewed by one of the authors (O.S.). Genotyping was performed, following amplification by polymerase chain reaction (PCR), using fragment analysis in a standard commercial setting (Applied Biosystems, USA). RESULTS: We have found a statistically significant association between rs6595788 polymorphism of CTXN3 gene and the risk of schizophrenia; the presence of AG genotype increased the risk 1.5-fold. Polymorphisms in DISC1 gene showed only marginally statistically significant association with schizophrenia (rs17817356) or no association whatsoever (rs821597 and rs980989) while two polymorphisms (rs9661837 and rs3737597) were found to be only slightly polymorphic in the samples. CONCLUSION: Evidence available in the literature suggests that altered expression of cortexin 3, either alone, or in parallel with changes in DISC1, could subtly perturb GABAergic neurotransmission and/or metabolism of amyloid precursor protein (APP) in developing brain, thus potentially exposing the affected individual to an increased risk of schizophrenia later in life.

• MeSH
• Alleles MeSH
• White People genetics   MeSH
• DNA genetics   MeSH
• Adult MeSH
• Gene Frequency MeSH
• Genetic Association Studies MeSH
• Genotype MeSH
• Risk Assessment MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Membrane Proteins genetics   MeSH
• Nerve Tissue Proteins genetics   MeSH
• Risk Factors MeSH
• Schizophrenia etiology   genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• CTXN3 protein, human MeSH Browser
• DISC1 protein, human MeSH Browser
• DNA MeSH
• Membrane Proteins MeSH
• Nerve Tissue Proteins MeSH