Identifying molecular pathways of olfactory dysfunction in Parkinson's disease through a systems biology framework

The sense of smell is essential for human perception. Olfactory function declines with increasing age, affecting a substantial portion of the elderly population, and this decline is more pronounced in men. This reduction can be attributed to anatomical and degenerative changes in the brain and olfactory receptors. There is robust clinical evidence indicating an association between olfactory perception decline/deficit (OPD) and major neurodegenerative diseases, with severe deficits observed in Alzheimer's and Parkinson's disease and milder effects noted in other conditions. However, its molecular bases have not yet been identified. Here, we explored the molecular connection between OPD and Parkinson's disease by conducting data-mining, gene enrichment analysis, and examining protein-interaction networks using systems biology approaches. We found pathways associated with both OPD and Parkinson's disease, identifying over 300 relevant genes. These genes belong to biologically relevant gene families, including transporters, kinases, nuclear receptors, transcription factors, and olfactory and other G protein-coupled receptors. Functional enrichment analysis revealed shared biological processes between OPD and Parkinson's disease, such as synaptic signalling and neuroinflammation. Mitochondrial gene enrichment was unique to Parkinson's. Both conditions exhibited a scarcity of associated genes on the Y chromosome but an even distribution on the non-pseudoautosomal region of the X chromosome, potentially explaining sex prevalence differences. In conclusion, our study suggests olfactory testing may help diagnose cognitive decline in neurodegenerative diseases. Further research is needed to understand the connection between OPD, aging, and other diseases and to examine olfactory performance in screening individuals at risk of Parkinson's disease and similar conditions.