α-Synuclein is genetically and neuropathologically linked to Parkinson’s disease. However, the mechanisms of known genetic toxicity modulators in a yeast model system remain largely unknown. In order to identify cellular rescue pathways at high-throughput, we have paired mass spectrometry-based monitoring of pathway activity and growth profiles through regression analysis. The results predicted a critical role for the protein Pah1 in lipid metabolism. Indeed, specific perturbation of Pah1 activity determines inclusion formation and toxicity thereby suggesting a potential target for combating pathologies associated with α-Synuclein accumulation.