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 be 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 artifacts. After correcting for cell composition, we identified a common signature that deregulated the previously unreported ammonium transport, as well as known biological processes including 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, and PRKN known to be related to PD; others with compelling evidence for their role in neurodegeneration, such as GSK3β, WWOX, and VPC; as well as novel potential players in the PD pathogenesis, including NTRK1, TRIM25, ELAVL1. Together, these data showed 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.