Transcriptomics analysis of post-mortem substantia nigra samples from Parkinson’s disease patients and controls.

The molecular mechanisms behind these disease-associated gender differences are still largely unknown, and a detailed understanding of the factors involved may open new avenues for pharmacological disease modification. Methods: To address this gap, we have conducted a meta-analysis of disease-associated molecular gender differences in brain transcriptomics data from PD case/control studies. We studied gender-dependent expression changes in individual genes and using systems level pathway and network analyses to identify coordinated gender-related molecular alterations. In each analysis, both gender-specific changes (significant alteration in only one gender) and gender-dimorphic changes (changes in both genders, but with opposite direction) were identified. Results: These analyses revealed significant disease-associated sex differences in immune response processes and mitochondrial pathways, and highlight regulatory factors, such as the transcription factor NR4A2, whose activity changes can explain ensuing alterations propagated through gene regulatory cascades. Overall, significant gender disparities were observed in PD-associated transcriptomic changes, resulting in coordinated modulations of molecular processes. Among the regulatory factors involved, NR4A2 has previously been reported to harbor rare mutations in familial PD and its pharmacological activation conferred neuroprotective effects in toxin-induced models of Parkinsonism. NR4A2 may therefore be of interest as a candidate target for further preclinical studies on addressing gender-related pathological features of PD.