Using a Drosophila rotenone-feeding model of sporadic PD, the study reports sex-specific gene expression changes across adult life stages and identifies pathways altered by toxin exposure that could serve as early transcriptional biomarkers.

By revealing sex-biased molecular responses to a mitochondrial toxin (rotenone), the work highlights candidate pathways/biomarkers and underscores the importance of sex as a variable for translational biomarker discovery and sex-aware therapeutic strategies in PD research.

Parkinson's disease (PD) is the second most common neurodegenerative condition characterized by dopaminergic neuronal loss in substantia nigra region of the brain. Sporadic PD cases have been attributed to exposure to toxins, such as rotenone. Prolonged exposure to rotenone presents itself with PD like symptoms including, but not limited to tremors, bradykinesia, and motor impairments. Similar to any other disease, PD is known to affect the global population in a gender-biased manner, where males are affected as much as 1.5-2 times more than females. Some of the molecular underpinnings of these differences have been reported, but not completely understood. We modelled sporadic form of PD in Drosophila melanogaster using a novel rotenone feeding approach and attempted to understand the gender specific genetic and molecular responses. Our model also exhibited gender biased response to rotenone exposure in PD symptoms and related pathophysiology. Analysis of gene expression from different pathways reveals that these differences are relevant at early as well as later stages of the adult fly life. Our study provides molecular insights into gender differences exhibited in pattern of neurodegeneration in sporadic PD models and helps identify pathways which are affected upon toxin exposure, which may aid as early transcriptional disease biomarkers for symptomatic cases.