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.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease
We evaluated whether the BRETIGEA-derived marker sets were enriched in the correct substantia nigra cell type using expression-weighted cell-type enrichment (EWCE) (Methods) (Supplementary Table S1)
Gene set enrichment analysis (GSEA) was performed using the Fast gene set enrichment analysis package version 1.12.0 [35], 100,000 permutations, with the Gene Ontology (GO) and the Canonical dataset downloaded from the Molecular Signatures Database (MSigDB)
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. This issue is concerning since it is not possible to distinguish between changes in genes that are highly expressed in a cell type whose proportions change and a genuine pathology-related transcriptional deregulation While the former might be interesting as it may correlate with disease progression, the latter can inform on the molecular mechanism for which therapeutic strategies might be devised. We systematically assessed the transcriptomic evidence for the presence of changes in cell compositions in the expression data of nine publicly available Parkinson’s disease-related microarrays of the substantia nigra (see Figure 1 for an overview). We conducted the first meta-analysis of these datasets while evaluating the impact of the cyto-architectural alterations on the differential expression analysis By correcting for these effects, we were able to detect genuine disease-related changes in the transcriptional landscape of the substantia nigra in PD patients. Six cell types using well-known markers: GFAP and GINS3 for the astrocytes; MOBP and MOG for the oligodendrocytes; CSF1R and OLR1 for the microglia; GAD1, GAD2, GABRA, SLC6A3, and TH for the neurons; VCAN for the oligodendrocyte precursor cells; LGALS1 and RGS5 for the endothelial cells
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