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 α-
synuclein, the
protein that forms amyloids in
Parkinson's disease, we here assessed the effects of
arsenic and
cadmium on α-
synuclein amyloid formation in vitro and in Saccharomyces cerevisiae (budding yeast) cells. Atomic force microscopy experiments with acetylated human α-
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 α-
synuclein demonstrated that
arsenic and
cadmium affected the distribution of α-
synuclein aggregates within the cells, reduced aggregate clearance, and aggravated α-
synuclein toxicity. Taken together, our in vitro data demonstrate that interactions between these two metals and α-
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 α-
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.