Correcting Differential Gene Expression Analysis for Cyto—Architectural Alterations in Substantia Nigra of Parkinson’s Disease Patients Reveals Known and Potential Novel Disease—Associated Genes and Pathways
Cells, vol. 11, pp. 198
Abstract
Several studies have analyzed gene expression profiles in the substantia nigra to better understand the pathological mechanisms causing Parkinson’s disease (PD). However, the concordance between the identified gene signatures in these individual studies was generally low. This might have been caused by a change in cell type composition as loss of dopaminergic neurons in the substantia nigra pars compacta is a hallmark of PD. Through an extensive meta-analysis of nine previously published microarray studies, we demonstrated that a big proportion of the detected differentially expressed genes was indeed caused by cyto-architectural alterations due to the heterogeneity in the neurodegenerative stage and/or technical artefacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes such as bioenergetic pathways, response to proteotoxic stress, and immune response. By integrating with protein interaction data, we shortlisted a set of key genes, such as LRRK2, PINK1, PRKN, and FBXO7, known to be related to PD, others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC, and novel potential players in the PD pathogenesis. Together, these data show the importance of accounting for cyto-architecture in these analyses and highlight the contribution of multiple cell types and novel processes to PD pathology, providing potential new targets for drug development.
Authors 6
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Affiliation as printed
Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
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Affiliation as printed
Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
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Affiliation as printed
Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
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Affiliation as printed
Erasmus MC, Department of Clinical Genetics, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands
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Leiden University Medical Center · Delft University of Technology
Affiliation as printed
Delft Bioinformatics Labaratory, Delft University of Technology, 2628 XE Delft, The Netherlands
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Leiden Computational Biology Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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Marcel J. T. Reinders corresponding Aachen Department of Human Genetics Leiden Computational Biology Center Section Molecular Epidemiology Department of Biomedical Data Sciences
Leiden University Medical Center · Delft University of Technology
Affiliation as printed
Delft Bioinformatics Labaratory, Delft University of Technology, 2628 XE Delft, The Netherlands
Department of Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Leiden Computational Biology Center, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
Section Molecular Epidemiology, Department of Biomedical Data Sciences, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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