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

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

Ferraro, F. (Erasmus MC)
Fevga, Christina (Erasmus MC)
Bonifati, Vincenzo (Erasmus MC)
Mandemakers, Wim (Erasmus MC)
Mahfouz, A.M.E.T.A. (TU Delft Pattern Recognition and Bioinformatics; Leiden University Medical Center)
Reinders, M.J.T. (TU Delft Pattern Recognition and Bioinformatics; Leiden University Medical Center)

2022

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.

Cyto-architecture
Interac-tome analysis
Meta-analysis
Parkinson’s disease
Transcriptome analysis

http://resolver.tudelft.nl/uuid:e07bc3f2-fbf0-4422-a05e-09cbd231b260

https://doi.org/10.3390/cells11020198

2073-4409

Cells, 11 (2)

Institutional Repository

journal article

© 2022 F. Ferraro, Christina Fevga, Vincenzo Bonifati, Wim Mandemakers, A.M.E.T.A. Mahfouz, M.J.T. Reinders