Effects of the toxic metals arsenite and cadmium on α-synuclein aggregation in vitro and in cells
Artikel i vetenskaplig tidskrift, 2021

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.

Cadmium toxicity

Arsenic toxicity

α-synuclein

Parkinson’s disease

Amyloid formation

Författare

Emma Lorentzon

Göteborgs universitet

Istvan Horvath

Chalmers, Biologi och bioteknik, Kemisk biologi

Ranjeet Kumar

Chalmers, Biologi och bioteknik, Kemisk biologi

Joana Isabel Rodrigues

Göteborgs universitet

Markus J. Tamás

Göteborgs universitet

Pernilla Wittung Stafshede

Chalmers, Biologi och bioteknik, Kemisk biologi

International Journal of Molecular Sciences

16616596 (ISSN) 14220067 (eISSN)

Vol. 22 21 11455

Ämneskategorier

Cellbiologi

Biofysik

Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)

DOI

10.3390/ijms222111455

Mer information

Senast uppdaterat

2021-11-09