Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting at least one out of every 100 people over the age of 60. PD is characterized by postural rigidity, resting tremors, and slowing of movements and thought processes. To date, the existing treatments for PD alleviate some symptoms, but neither affect its underlying pathology nor delay its progression. The pathologic hallmark of PD is the formation of Lewy bodies (LBs) within degenerating neurons. A major component of LBs is α-synuclein (α-syn), a small synaptic lipid-interacting protein of unknown function. α-Syn is implicated in dominantly inherited forms of PD and the closely related diseases dementia with Lewy bodies and multiple systems atrophy. These diseases also feature profound mitochondrial dysfunction and oxidative stress resulting from exposure to either metals or environmental toxins. Despite a decade of research, the mechanisms by which α-syn mediates neurotoxicity remain poorly understood and it is still unclear how α-syn toxicity is related to mitochondrial dysfunction.

In this study, the authors report a slightly higher toxicity α-syn strain (HiTox), which exhibits strong mitochondrial defects in addition to the ER-to-Golgi trafficking defects they had previously described in their yeast model system. Transcriptional profiling revealed that many genes involved in mitochondrial function were significantly altered in cells overexpressing α-syn well before cells began to die. These yeast cells had abnormal mitochondrial morphology and exhibited oxidative stress.

Chemical screening of the HiTox strain identified a family of compounds that are potent suppressors of α-syn toxicity. These molecules reversed the adverse cellular features associated with α-syn toxicity, including ER-to-Golgi trafficking defects, abnormal mitochondrial morphology and oxidative stress. Moreover, these compounds antagonized α-syn toxicity in dopaminergic neurons of C. elegans and in rat primary neuronal cultures. These compounds also rescued rat primary neurons from rotenone toxicity, which has been used to model mitochondrial dysfunction in PD.

This work establishes a direct link between α-syn, ER-to-Golgi trafficking defects and mitochondrial dysfunction. This suggests that α-syn acts on a deeply rooted biological process crucial to neuronal viability. Moreover, the identification of novel compounds capable of antagonizing α-syn toxicity in different model systems spanning a billion years of evolution from yeast to mammals highlights the strength of using the simple model organism S. cerevisiae to investigate complex biological questions about human disease.