Effects of the Toxic Metals Arsenite and Cadmium on alpha-Synuclein Aggregation In Vitro and in Cells

Exposure to heavy metals, including arsenic and cadmium, is associated with neurodegenerative disorders such as Parkinson's disease. However, the mechanistic details of how these metals contribute to pathogenesis are not well understood. To search for underlying mechanisms involving alpha-synuclein, the protein that forms amyloids in Parkinson's disease, we here assessed the effects of arsenic and cadmium on alpha-synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human alpha-synuclein demonstrated that amyloid fibers formed in the presence of the metals have a different fiber pitch compared to those formed without metals. Both metal ions become incorporated into the amyloid fibers, and cadmium also accelerated the nucleation step in the amyloid formation process, likely via binding to intermediate species. Fluorescence microscopy analyses of yeast cells expressing fluorescently tagged alpha-synuclein demonstrated that arsenic and cadmium affected the distribution of alpha-synuclein aggregates within the cells, reduced aggregate clearance, and aggravated alpha-synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and alpha-synuclein modulate the resulting amyloid fiber structures, which, in turn, might relate to the observed effects in the yeast cells. Whilst our study advances our understanding of how these metals affect alpha-synuclein biophysics, further in vitro characterization as well as human cell studies are desired to fully appreciate their role in the progression of Parkinson's disease.