Geraniol protects against oxidative stress and proteotoxicity in C. elegans Parkinson's disease models

Abstract

Due to the escalating life expectancy, the prevalence of age-related disorders like neurodegenerative diseases (ND) has surged. Oxidative stress (OS) has emerged as a key accelerator in ND progression. In Parkinson’s disease (PD), for instance, compromised free radical scavenging capacity has been linked to worsened α-synuclein ag- gregation and proteotoxic damage. Geraniol (GER), a plant-derived essential oil, has recognized antioxidant properties. Considering that OS contributes to ND progression, compounds with antioxidant activity have been postulated as potential therapeutic agents. Leveraging the suitability of Caenorhabditis elegans as a model organism in biomedical research due to its genetic homology with mammals, including cytoprotective proteins, we aim to assess GER’s biological efficacy in a C. elegans PD model and delve into the underlying molecular mechanisms. Our results first confirmed the in vivo antiox- idant activity of GER. We cultured wild-type animals with GER and then exposed them to Juglone (oxidative agent). Locomotion was employed as a survival proxy using the Worm MicroTracker device. Strikingly, GER exhibited a significant increase in animal survival under OS conditions (P=<0.001). To unravel the precise mechanism driving GER’s protective effects, we analyzed null mutants within key molecular pathways associated with OS response. Intriguing- ly, our preliminary findings showed that either DAF16/FOXO, HSF1 or SKN1/NRF2 are involved in mediating GER’s protective effect. Given the link between OS and PD, we also evaluated the GER´s impact within a C. elegans PD model. We found that GER improves the impaired-locomotion phenotype of this model (P = 0,011). So far, these results indicate a potential antiproteotoxic effect of GER in C. elegans PD models. To comprehensively dissect GER’s effects, we propose an integrative approach involving genetic analyses, advanced microscopy techniques, and behavioral assessments.