Subject(s)
Creutzfeldt-Jakob Syndrome , Genetic Predisposition to Disease , Insomnia, Fatal Familial , Mutation/genetics , Aged , Asian People , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/genetics , Female , Humans , Insomnia, Fatal Familial/cerebrospinal fluid , Insomnia, Fatal Familial/genetics , Male , Middle AgedABSTRACT
Prion diseases are a group of fatal neurodegenerative disorders that affect humans and animals. Besides of the pathological agent, prion, there are some elements that can influence or determine susceptibility to prion infection and the clinical phenotype of the diseases, e.g., the polymorphism in PRNP gene. Another polymorphism in ZBTB38-RASA2 has been observed to be associated with the susceptibility of sporadic Creutzfeldt-Jacob disease (sCJD) in UK. MicroRNAs are endogenous small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. In this study, two polymorphic loci in miR-146a (rs2910164 and rs57095329) and one locus in ZBTB38-RASA2 (rs295301) of 561 Chinese patients of sCJD and 31 cases of fatal familial insomnia (FFI) were screened by PCR and sequencing. Our data did not figure out any association of those three SNPs with the susceptibility of sCJD. However, a significant association of the SNP of rs57095329 in miR-146a showed the association with the susceptibility of FFI. Additionally, the SNP of rs57095329 showed statistical significances with the appearances of mutism and the positive of cerebrospinal fluid (CSF) protein 14-3-3 in sCJD patients, while the SNP of ZBTB38-RASA2 was significantly related with the appearance of myoclonus in sCJD patients. It indicates that the SNPs of ZBTB38-RASA2 and miR-146a are not associated with the susceptibility of the Chinese sCJD patients, but may influence the appearances of clinical manifestations somehow.
Subject(s)
Creutzfeldt-Jakob Syndrome/genetics , Encephalopathy, Bovine Spongiform/genetics , Insomnia, Fatal Familial/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide , Repressor Proteins/genetics , ras GTPase-Activating Proteins/genetics , 14-3-3 Proteins/genetics , Aged , Asian People , Creutzfeldt-Jakob Syndrome/blood , Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/diagnosis , Disease Susceptibility , Encephalopathy, Bovine Spongiform/blood , Encephalopathy, Bovine Spongiform/cerebrospinal fluid , Encephalopathy, Bovine Spongiform/diagnosis , Gene Frequency , Genotype , Humans , Insomnia, Fatal Familial/blood , Insomnia, Fatal Familial/cerebrospinal fluid , Insomnia, Fatal Familial/diagnosis , Middle Aged , Myoclonus/genetics , Odds RatioABSTRACT
The alteration of protein tau in the cerebrospinal fluid (CSF) of Creutzfeldt-Jakob disease (CJD) has been widely evaluated, possessing a significant diagnostic value for CJD. With the biotin-labeled tau-exon-specific mAbs, direct ELISA methods were established and the levels of tau isoforms containing exon-2 and exon-10 segments in CSF of the patients with various human prion diseases and in brain tissues of scrapie-infected animals were evaluated. The results showed that the levels of tau, especially containing four repeats in microtubule binding domain, were increased in the CSF samples of the patients with sporadic CJD (sCJD). Using the unlabeled (cold) mixed exon-specific mAbs, a competitive tau ELISA was conducted based on a commercial tau kit. It revealed that the majority of the increased tau in the CSF of sCJD cases was derived from the tau isoforms with exon-2 and exon-10 segments. Increases of CSF tau isoforms with exon-2 and exon-10 segments were also observed in the patients of E200K and T188K genetic CJD (gCJD), but not in the cases of fatal familiar insomnia (FFI). The increasing levels of tau isoforms with exon-2 and exon-10 segments in the group of sCJD correlated well with the positive 14-3-3 in CSF. Additionally, the similar alterative profiles of tau isoforms with exon-2 and exon-10 segments were also observed in the brain tissues of scrapie-infected rodents and a sCJD patient. Our data here propose the tau isoforms with exon-2 and exon-10 segments increase in CSF of sCJD and some types of gCJD, which may help to understand the physiological metabolism and pathological significance of various tau isoforms in the pathogenesis of prion diseases.
Subject(s)
Creutzfeldt-Jakob Syndrome/cerebrospinal fluid , Creutzfeldt-Jakob Syndrome/genetics , Exons/genetics , tau Proteins/cerebrospinal fluid , 14-3-3 Proteins/metabolism , Adult , Aged , Aged, 80 and over , Animals , Brain/metabolism , Brain/pathology , Case-Control Studies , Demography , Enzyme-Linked Immunosorbent Assay , Female , Humans , Insomnia, Fatal Familial/cerebrospinal fluid , Insomnia, Fatal Familial/genetics , Male , Mesocricetus , Middle Aged , Protein Isoforms/cerebrospinal fluid , Protein Isoforms/genetics , Scrapie/cerebrospinal fluid , tau Proteins/geneticsABSTRACT
The 14-3-3 protein test has been shown to support the clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) when associated with an adequate clinical context, and a high differential potential for the diagnosis of sporadic CJD has been attributed to other cerebrospinal fluid (CSF) proteins such as tau protein, S100b and neuron specific enolase (NSE). So far there has been only limited information available about biochemical markers in genetic transmissible spongiform encephalopathies (gTSE), although they represent 10-15% of human TSEs. In this study, we analyzed CSF of 174 patients with gTSEs for 14-3-3 (n = 166), tau protein (n = 78), S100b (n = 46) and NSE (n = 50). Levels of brain-derived proteins in CSF varied in different forms of gTSE. Biomarkers were found positive in the majority of gCJD (81%) and insert gTSE (69%), while they were negative in most cases of fatal familial insomnia (13%) and Gerstmann-Sträussler-Scheinker syndrome (10%). Disease duration and codon 129 genotype influence the findings in a different way than in sporadic CJD.