Huntington's disease (HD) and Parkinson's disease (PD) are neurodegenerative diseases (NDs) in which protein misfolding/accumulation are associated with neuronal dysfunction and loss. HD is a hereditary disease caused by the expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene. Although the number of repeats correlates with the severity of the disease, there is still variability amongst individuals with the same number of repeats. PD is the second most common ND and, although there are familial forms, most PD cases are sporadic, caused by a combination of environmental and genetic risk factors, one of which is the SNCA gene that encodes α-Synuclein (αSyn). To find candidate genetic modifiers responsible for the variability in severity/risk in HD and PD, quantitative trait loci (QTL) analysis was performed in yeast. The effect of mutant HTT (mHTT) and αSyn on growth was assessed in 14 genetically diverse natural isolates using PHENOS - a software that allows the analysis of yeast growth on solid media -. The strains that showed the most extreme phenotypes (SX1, HN6 and BJ20) were intercrossed to generate a large population of stains with new combinations of alleles. The QTL analysis was performed using the effect on growth of mHTT and αSyn separately, and the possible modifier genes that were present in both lists were further validated in yeast and fruit flies by overexpressing or downregulating them. Through this work we identified four genes whose deletion enhanced the toxicity of the proteins: PPM1 and TIF6 enhanced both mHTT and αSyn toxicity, while PER1 and GIN4 only enhanced αSyn toxicity. The overexpression (OE) of TIF6 was protective against mHTT and αSyn toxicity in yeast. In conclusion, these four genes, specially TIF6, are interesting therapeutic targets for HD and PD and should be validated in more complex models.
