Klein Posternack, Andrés DavidCubillos Riffo, Francisco AlbertoRubilar Espinoza, Juan Carlos2024-11-122024-11-122024https://hdl.handle.net/11447/9388Thesis submitted to the Faculty of Medicine of the Universidad del Desarrollo for the Academic Degree of Doctor of Science and Innovation in MedicineParaquat (PQ) is a potent herbicide that induces oxidative stress and mitochondrial dysfunction. In humans, it is highly toxic, and it can induce Parkinson's Disease (PD). PD is a chronic and progressive neurodegenerative disease, with a worldwide prevalence of 315 per 100,000 people of all ages. Recent studies have revealed that neurons from PD patients exhibit stress responses, mitochondrial dysfunction, and metabolic deficits involving ATP and nicotinamide adenine dinucleotide (NAD+). While studies have demonstrated the potential of nicotinamide riboside (NR) to mitigate age- and disease-related metabolic decline in PD, the specific effects of NR on PD induced by pesticide exposure, such as paraquat, have not been extensively explored. Saccharomyces cerevisiae is a model organism that has allowed the study of relevant biological processes over time. It exhibits remarkable genetic diversity, making it an ideal model for studying the genetic basis of phenotypic variation. In this study, we hypothesized that genetically diverse Saccharomyces cerevisiae strains exposed to paraquat exhibit cellular and molecular responses that reveal potential modifier genes associated with its toxicity. We treated 1,011 isolates and 96 segregants from the cross of SA x WE founder Saccharomyces cerevisiae strains with PQ (75 μg/mL). We measured their growth curves and calculated the specific growth rate (μMax), used as a phenotypic trait for the genome-wide association studies (GWAS) and quantitative trait loci (QTL) mapping. We performed mixed-model association analysis using FaST-LMM for GWAS and linkage analysis using R/qtlsoftware, calculating LOD scores with a nonparametric model. We used diploid strains (603 isolates) for GWAS and 96 segregants for QTL mapping, identifying variants and markers that exceeded the significance threshold. Using these variants and markers, we identified candidate genes for validation. We validated NRT1 in a yeast mutant and subsequently showed that NR treatment provided significant protection against PQ-induced damage in both S288C yeast and iPSC-derived dopaminergic neurons from GBA-PD patients. In conclusion, this study provides valuable insights into the genetic and metabolic factors underlying PQ resistance in S. cerevisiae. The findings highlight the importance of NAD+ metabolism and mitochondrial function in mitigating the toxic effects of PQ. The identification of Nrt1 as a key transporter of NR, suggests potential therapeutic targets for interventions aimed at preventing or treating PQ-induced toxicity in PD.125 p., review articleen090036SParaquatSaccharomyces cerevisiaeParkinson's diseaseherbicidesNAD+ metabolismThesishttps://doi.org/10.52611/11447/9388