Phenotypic cell-based models of neurodegenerative disease can be useful for drug screening, but progress has been hampered by the difficulty of establishing robust neuronal phenotypes. Accumulation of α-synuclein (α-syn) is associated with Parkinson's disease; two studies now take advantage of cellular responses to overexpression of α-syn that are conserved from yeast to humans to identify a neuroprotective compound and to determine its mechanism of action. Tardiff et al. showed that, in yeast, α-syn expression disrupts endosomal transport and alters mitochondrial function (hallmarks of α-synucleinopathies such as Parkinson's disease). A drug screen revealed that these phenotypes were rescued by N-aryl benzimidazole (NAB) treatment. NAB was shown to be neuroprotective against α-syn toxicity in human neurons by activating the E3 ubiquitin ligase NEDD4 pathway. Similarly, Chung et al. found that both yeast overexpressing α-syn and neurons derived from a patient carrying a highly penetrant form of α-syn exhibited endoplasmic reticulum and nitrosative stress, and that these effects were rescued by NAB or its target, NEDD4 or Rsp5 (the yeast NEDD4 homologue). These papers demonstrate the utility of yeast-based screens in helping to identify novel compounds that might have neuroprotective benefits in Parkinson's disease.