title: Network analysis of human post-mortem microarrays reveals novel genes, microRNAs, and mechanistic scenarios of potential importance in fighting huntington's disease.
abstract: Huntington's disease is a progressive neurodegenerative disorder characterized by motor disturbances, cognitive decline, and neuropsychiatric symptoms. In this study, we utilized network-based analysis in an attempt to explore and understand the underlying molecular mechanism and to identify critical molecular players of this disease condition. Using human post-mortem microarrays from three brain regions (cerebellum, frontal cortex and caudate nucleus) we selected in a four-step procedure a seed set of highly modulated genes. Several protein-protein interaction networks, as well as microRNA-mRNA networks were constructed for these gene sets with the Elsevier Pathway Studio software and its associated ResNet database. We applied a gene prioritizing procedure based on vital network topological measures, such as high node connectivity and centrality. Adding to these criteria the guilt-by-association rule and exploring their innate biomolecular functions, we propose 19 novel genes from the analyzed microarrays, from whichCEBPA,CDK1,CX3CL1,EGR1,E2F1,ERBB2,LRP1,HSP90AA1 andZNF148might be of particular interest for experimental validation. A possibility is discussed for dual-level gene regulation by both transcription factors and microRNAs in Huntington's disease mechanism. We propose several possible scenarios for experimental studies initiated via the extra-cellular ligands TGFB1, FGF2 and TNF aiming at restoring the cellular homeostasis in Huntington's disease.
authors.affiliation: Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Sreedevi
authors.initials: S
authors.lastname: Chandrasekaran
authors.affiliation: Center for the Study of Biological Complexity, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Danail
authors.initials: D
authors.lastname: Bonchev
keywords: Computational molecular neurobiology; Huntington's disease; Microarray analysis; Protein interaction network; Transcriptome; miRNAs