title: Computational deconvolution of genome wide expression data from Parkinson's and Huntington's disease brain tissues using population-specific expression analysis.
abstract: The characterization of molecular changes in diseased tissues gives insight into pathophysiological mechanisms and is important for therapeutic development. Genome-wide gene expression analysis has proven valuable for identifying biological processes in neurodegenerative diseases using post mortem human brain tissue and numerous datasets are publically available. However, many studies utilize heterogeneous tissue samples consisting of multiple cell types, all of which contribute to global gene expression values, confounding biological interpretation of the data. In particular, changes in numbers of neuronal and glial cells occurring in neurodegeneration confound transcriptomic analyses, particularly in human brain tissues where sample availability and controls are limited. To identify cell specific gene expression changes in neurodegenerative disease, we have applied our recently published computational deconvolution method, population specific expression analysis (PSEA). PSEA estimates cell-type-specific expression values using reference expression measures, which in the case of brain tissue comprises mRNAs with cell-type-specific expression in neurons, astrocytes, oligodendrocytes and microglia. As an exercise in PSEA implementation and hypothesis development regarding neurodegenerative diseases, we applied PSEA to Parkinson's and Huntington's disease (PD, HD) datasets. Genes identified as differentially expressed in substantia nigra pars compacta neurons by PSEA were validated using external laser capture microdissection data. Network analysis and Annotation Clustering (DAVID) identified molecular processes implicated by differential gene expression in specific cell types. The results of these analyses provided new insights into the implementation of PSEA in brain tissues and additional refinement of molecular signatures in human HD and PD.
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester Leicester, UK.
authors.forename: Alberto
authors.initials: A
authors.lastname: Capurro
authors.affiliation: Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University of Bonn Bonn, Germany ; Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland St Lucia, QLD, Australia.
authors.forename: Liviu-Gabriel
authors.initials: LG
authors.lastname: Bodea
authors.affiliation: DFG-Center for Regenerative Therapies Dresden Dresden, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Schaefer
authors.affiliation: Department of Cell Physiology and Pharmacology, University of Leicester Leicester, UK.
authors.forename: Ruth
authors.initials: R
authors.lastname: Luthi-Carter
authors.affiliation: The Bioinformatics Core and The Synaptic Neurobiology Laboratory, The Florey Institute of Neuroscience and Mental Health Parkville, VIC, Australia.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Perreau
keywords: Huntington's disease; Parkinson's disease; autophagy; computational deconvolution; microarray; transcriptomic analysis