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[O2–03–02]: PROTEIN NETWORK ANALYSIS TO PRIORITIZE CANDIDATE GENES AND PATHWAYS FOR SPORADIC DISEASE: A COMPARISON BETWEEN FRONTOTEMPORAL DEMENTIA AND PARKINSON's DISEASE
Author(s) -
Manzoni Claudia,
Ferrari Raffaele,
Kia Demis,
Lovering Ruth C.,
Hardy John,
Lewis Patrick A.
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.156
Subject(s) - frontotemporal dementia , genome wide association study , candidate gene , neurodegeneration , biology , computational biology , genetics , omim : online mendelian inheritance in man , gene , disease , in silico , mendelian inheritance , dementia , phenotype , single nucleotide polymorphism , medicine , pathology , genotype
Our understanding of the pathological events and the molecular transition from the asymptomatic phase (AsymAD) to clinical dementia is limited. Although amyloid-beta (Ab) deposition in the brain is thought to be a central force driving AD pathogenesis, humans remain cognitively normal for many years despite accumulating aggregates of Ab plaques and tau neurofibrillary tangles. Systems-level analyses of large data sets have emerged as essential tools for identifying key molecular pathways and potential new drug targets. Here we present a large-scale protein co-expression network analysis of human postmortem brain to identify processes involved in AD pathogenesis and to prioritize their links to relevant clinical, neuropathological and genetic risk factors. Methods:Using quantitative liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) we comparatively analyzed the total brain proteomes of 47 post-mortem frontal cortex samples (Brodmann Area 9) representing cognitively normal individualswithoutADpathology (n1⁄413), cognitively normal asymptomatic individuals (AsymAD; n1⁄414) and cognitively impaired individuals with AD pathology (n1⁄420). Tau and Ab pathological burden was scored mild to moderate in all AsymAD and severe in AD cases. Using isobaric tandem-mass tags (TMT) following off-line fractionation a total of 6,534 proteins were identified and quantified across all 47 individual cases. WeiGhted Co-expression Network Analysis (WGCNA) defined protein modules linked to pathways, and cell-types across the individual cases. Results: Network analysis revealed 50 modules of co-expressed proteins, 18 of which correlated with cognitive decline and/or AD neuropathology. A subset of modules overlapped with previously generated RNA coexpression networks, including those associatedwith neurons and astroglial cell types, showing altered expression in AD, even in asymptomatic stages. AD genetic risk loci were concentrated in glial-related modules in the proteome and transcriptome consistent with their causal role in AD. Conclusions: This proteome wide co-expression network approach reveals proteinand disease-specific pathways involved in the etiology, initiation, and progression of AD.