Title : C. Elegans as a platform for studying neurodegenerative diseases: identification of antioxidants as therapeutics agents
Abstract:
The increase in life expectancy has led to a rise in age-related disorders, including neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Oxidative stress (OS) plays a crucial role in the progression of these conditions, as impaired free radical scavenging can result in protein aggregation and subsequent proteotoxic damage. Given the established association between OS and NDs, antioxidant compounds represent a promising avenue for therapeutic intervention. In this study, we utilized C. elegans models for NDs to evaluate the in vivo antioxidant properties and protective effects against neuronal protein aggregation of both synthetic and natural compounds. Our approach integrated genetic, microscopy, pharmacological, and behavioral techniques to elucidate the molecular mechanisms underlying these effects in C. elegans models. We identified a synthetic imidazole derivative, 1-Mesityl-3-(3-Sulfonatopropyl) Imidazolium (MSI), and the natural compound geraniol as enhancers of OS resistance in C. elegans. Given the established link between antioxidant potential and anti-proteotoxic capacity, we further assessed the impact of these compounds in C. elegans models of AD, PD, and HD. Our results show that these compounds delay or prevent the onset of proteotoxic phenotypes associated with these NDs and reduce both protein aggregation and neurodegeneration. To better understand the protective mechanisms, we analyzed null mutants in key OS-related pathways. Our findings indicate that the transcription factor HSF-1 is essential for mediating the protective effects of MSI, while SKN-1/Nrf-2 specifically contributes to the protective actions of geraniol. Microscopy analysis also suggests that geraniol may promote autophagy, further contributing to its neuroprotective effects. This study highlights the value of C. elegans as a model system for conducting accessible pharmacological assays aimed at identifying compounds with therapeutic potential. Our findings demonstrate that compounds with in vivo antioxidant properties also exhibit anti-proteotoxic and anti-neurodegenerative effects, underscoring the promise of antioxidants as effective agents against proteotoxicity.
