Abstract
Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases.
Highlights
From the ‡State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Chang-Bai Rd 155, Beijing 102206, People’s Republic of China; §Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
Global Protein Profiling of the Brain Regions from Different Human Prion Diseases—To screen the potential difference in brain protein expressions among human prion diseases and normal control, stored postmortem brain tissues of the cortex and cerebellum regions of the patients with sporadic CJD (sCJD), fatal familial insomnia (FFI), G114V genetic CJD (gCJD), and normal control were separately subjected into Isobaric tags for relative and absolute quantitation (iTRAQ) based proteomic study
Considering we utilized an established algorithm for analyzing iTRAQ data [15], we did not set up the paralleled controls
Summary
Patients—Human cortex and cerebellum samples collected from the patients with definitely diagnosed sCJD, FFI, or G114V gCJD were enrolled in this study. The sCJD patient was an 80-year-old man with progressive disturbance of consciousness. One month later, he developed obvious akinetic mutism and inactivity, and subsequently many other symptoms appeared such as alalia, apathy, drowsiness, and pyramidal symptoms. Two different HPLC approaches were adopted, high-pH RP and strong cation exchange (SCX). In the SCX HPLC procedure, the peptides were loaded onto a SCX column (Luna SCX, 4.6 mm ϫ 250 mm, Phenomenex), and eluted by a step linear elution program, 0 –10 min equilibrated in buffer A
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