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Analysis of RNA expression profiles identifies dysregulated vesicle trafficking pathways in Creutzfeldt-Jakob Disease

ABSTRACT: Functional genomics applied to the study of RNA expression profiles identified several abnormal molecular processes in experimental prion disease. However, only a few similar studies have been carried out to date in a naturally occurring human disease. To better characterize the transcriptional cascades associated with sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, we investigated the global gene expression profile in the frontal cortices of 10 patients with sCJD and 10 non-neurological controls by microarray analysis. The comparison identified 333 highly differentially expressed genes (hDEGs) in sCJD. Functional enrichment Gene Ontology analysis revealed that hDEGs were mainly associated with synaptic transmission, including GABA (q-value=0.049) and glutamate (q-value=0.005) signalling, and the immune/inflammatory response. Furthermore, the analysis of cellular components performed on hDEGs showed a compromised regulation of vesicle-mediated transport with mainly up-regulated genes related to the endosome (q-value=0.01), lysosome (q-value=0.04), and extracellular exosome (q-value<0.01). A targeted analysis of the retromer core component VPS35 (Vacuolar protein sorting-associated protein 35) showed a down-regulation of its gene expression (p=0.006) and protein levels (p=0.002). Taken together these results confirm and expand previous microarray expression profile in CJD. Most significantly, they also demonstrate the involvement of the endosomal-lysosomal system. Since the latter is a common pathogenic pathway linking together diseases such as Alzheimer’s and Parkinson’s, it could be the focus of future studies aimed at identifying new therapeutic targets in neurodegenerative diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE124571 | GEO | 2019/01/03

REPOSITORIES: GEO

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Project description:The familial or genetic Creutzfeldt-Jakob disease (fCJD or gCJD) is the inherent form of human prion diseases, which accounts for approximately 10-15% of human prion diseases that are caused by mutations of the prion protein gene (PRNP). In this study, the global expression patterns of the parietal cortex from a patient with G114V gCJD were comparatively analyzed with the normal controls by using a commercial human genome expression chip. Totally 8774 genes showed differential expression, among them 2769 genes were upregulated and 6005 ones were downregulated. The reliability of the results was confirmed by the real-time RT-PCR assays for several specific genes. The most differentially expressed genes involved in the functions of regulation of transcription, ion transport, transcription, cell adhesion, signal transduction. The gene associated with gliosis was upregulated and the genes marked for neurons were downregulated, while the transcription of PRNP gene maintained unchanged. 169 different pathways showed significantly changed in the brain of G114V gCJD. The most significantly regulated pathways included that of Alzheimer’s and Parkinson’s disease, oxidative phosphorylation, regulation of actin cytoskeleton, MAPK signaling pathway and proteasome, which were described in prion diseases previously. In addition, some rarely addressed pathways in prion diseases, such as axon guidance, gap junction and purine metabolism, were also significantly changed in G114V gCJD. The transcriptional situations of the most genes in the top ten changed pathways were down-regulated. The extensive reductions of gene expressions in G114V gCJD showed the comparable profiles with sporadic CJD. The data here raised the useful clues for understanding the pathogenesis of the disease and selecting the potential biomarkers for diagnostic and therapeutic tools. Brain tissues of parietal cortex from a definitely diagnosed G114V gCJD were enrolled into this study. The patient was a 47-year-old Han-Chinese woman at the onset. Neuropathological assays of ten different brain regions revealed typical sCJD-like abnormality and PrPSc deposits. Meanwhile, a commercial normal human parietal cortex total RNA (Clontech) pooled from four male/female aged 35-89 was utilized as control.

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Analysis of RNA expression profiles identifies dysregulated vesicle trafficking pathways in Creutzfeldt-Jakob Disease

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