Global transcriptional profiling of the postmortem brain of a patient with G114V genetic Creutzfeldt-Jakob disease

Abstract

Abstract. Familial or genetic Creutzfeldt-Jakob disease (fCJD or gCJD) is an inherent human prion disease caused by mutation of the prion protein gene (PRNP). In the present study, global expression patterns of the parietal cortex from a patient with G114V gCJD were analyzed using the Affymetrix Human Genome U133+ 2.0 chip with a commercial normal human parietal cortex RNA pool as a normal control. In total, 8,774 genes showed differential expression; among them 2,769 genes were upregulated and 6,005 genes were downregulated. The reliability of the results was confirmed using real-time RT-PCR assays. The most differentially expressed genes (DEGs) were involved in transcription regulation, ion transport, transcription, cell adhesion, and signal transduction. The genes associated with gliosis were upregulated and the genes marked for neurons were downregulated, while the transcription of the PRNP gene remained unaltered. A total of 169 different pathways exhibited significant changes in the brain of G114V gCJD. The most significantly regulated pathways included Alzheimer's and Parkinson's disease, oxidative phosphorylation, regulation of actin cytoskeleton, MAPK signaling and proteasome, which have previously been linked to prion diseases. In addition, we found some pathways that have rarely been explored in regards to prion diseases that were also significantly altered in G114V gCJD, such as axon guidance, gap junction and purine metabolism. The majority of the genes in the 10 most altered pathways were downregulated. The data of the present study provide useful insights into the pathogenesis of G114V gCJD and potential biomarkers for diagnostic and therapeutic purposes. IntroductionPrion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders in humans and animals, including Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathies (BSEs) in cattle, and scrapie in sheep and goats. The conversion of prion protein (PrP), coded by the PRNP gene, from its cellular isoform PrP C to its pathogenic isoform PrP Sc through a post-translational process is considered the etiology of these diseases. As a result of the conversion, the portion of β-sheets within PrP is increased (from 3 to 45%) whereas that of α-helices decreases (from 42 to 30%), therefore causing PrP to become detergent insoluble and resistant to denaturant (isoform PrP Sc ) (1). The conversion also causes a series of histopathological changes, including the depositions of PrP Sc , spongiform degenerations, neuronal loss and astrogliosis.According to the pathomechanisms, CJD can be classified into sporadic CJD (sCJD), familial or genetic CJD (fCJD or gCJD) and iatrogenic CJD (iCJD). fCJD accounts for approximately 10-15% of all CJD cases, characterized by the genetic changes of PrP (2). To date, 56 different mutations, including residue substitutions, insertions and deletions, have been reported (3). For instance, proline to leucine mutation at the 102nd position (P102L) ...

Activation of the AMPK-ULK1 pathway plays an important role in autophagy during prion infection

“…In response to energy depletion, such as glucose starvation, TORC1 is inhibited by AMPK and autophagy is stimulated 42 . Our previous analyses of global gene expression profiles in brain tissues of humans with genetic TSEs showed that almost half of the affected cellular pathways are metabolism-associated, such as amino acid metabolism, energy metabolism and lipid metabolism 43 44 . Neuronal defects in glucose uptake and metabolism following reductions in the glucose transporter 3 (GLUT3) are commonly observed in various scrapie-infected rodent models and in the scrapie-infected cell line SMB-S15 45 .…”

Proteomics Analyses for the Global Proteins in the Brain Tissues of Different Human Prion Diseases*

“…It highlights that although the etiological agents and the pathogenesis may differ from each other, the global proteomic profiles in brain tissues of the three human TSEs at terminal stage possess great similarity. Interestingly, the pathways of PD, AD, and oxidative phosphorylation are also the most significantly changed ones in the assays of the global gene expression patterns in the thalamus and parietal lobe of the three Chinese FFI cases ( 6 ) and in the parietal lobe of a Chinese G114V gCJD patient ( 7 ). Such phenomena are also detected when we comparatively analyze the global transcriptional profiles in the cortex regions of Caucasian sCJD patients ( 27 ) and Chinese FFI cases ( 28 ).…”

“…During the long-term pathogenesis of human TSEs, besides of accumulation of PrP Sc in brain tissues, numerous brain proteins, which are involved in many different biological processes and pathways, have been described to be abnormally changed ( 3 , 4 , 5 ). Recently, the global transcriptional profiles in the brain tissues of some kinds of human TSEs, for example, sCJD, gCJD, and FFI have been reported with the help of high throughput microarray technique ( 6 , 7 ). However, the global changes of proteins in the brain tissues, which are definitely important for understanding the pathogenesis of the disease and providing the clues for the disease diagnosis and therapy, remains seldom addressed.…”

Global profiles of a cetylated proteins in the brains of scrapie agents 139A- and ME7-infected mice collected at mid-early, mid-late and terminal stage

“…The etiological agent is prion, a very unique pathogen without nucleic acid. Beside of the neuropathological hallmarks of prion disease, such as deposits of prions (PrP Sc ), neuron loss and gliosis, numerous abnormalities of biological pathways in the central nerve system (CNS) have been identi ed, e.g., increased in ammatory reactions, activated autophagy, obvious apoptosis [2][3][4][5], which result from the aberrant alterations of the transcriptions and expressions of a large quantity of proteins and enzymes in the brains veri ed by the assays of transcriptomics and proteomics [6][7][8][9]. Moreover, the abnormal changes of post-translational modi cations for brain proteins have been repeatedly described in the CNS tissues of various neurodegenerative diseases, involving in phosphorylation, S-nitrosylation, ubiquitylation, O-GlcNAcylation, acetylation, etc.…”