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

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.

A Systematic Review of Extracellular Matrix-Related Alterations in Parkinson’s Disease

“…Second, this review excluded studies that did not report significant ECM-related findings, as per the search criteria. A subsequent exploratory literature search designed to identify omics studies in PD that did not identify ECM-related pathways as top hits resulted in more than 20 studies [ 45 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 ]. However, upon closer review of these studies, it was noted that some limited the proteins or pathways that were included in the final models/reports for various reasons and, therefore, may not be expected to find ECM alterations (e.g., removal of genes expressed at low levels [ 112 ], inclusion limited to pathways with established relevance to PD [ 117 ]).…”

“…However, upon closer review of these studies, it was noted that some limited the proteins or pathways that were included in the final models/reports for various reasons and, therefore, may not be expected to find ECM alterations (e.g., removal of genes expressed at low levels [ 112 ], inclusion limited to pathways with established relevance to PD [ 117 ]). Several other excluded studies reported significant findings for one or more individual ECM components rather than as part of a gene set [ 45 , 114 , 115 ] or as a significant interaction pathway rather than as part of a primary altered pathway [ 126 ]. Thus, although a substantial number of published omics studies do not report ECM-related pathways as significant, there is still ample reason to suspect their involvement and alteration.…”