Effects of the Toxic Metals Arsenite and Cadmium on α-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 α-synuclein, the...
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MDPI AG
2021-10-01
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| author | Emma Lorentzon Istvan Horvath Ranjeet Kumar Joana Isabel Rodrigues Markus J. Tamás Pernilla Wittung-Stafshede |
| author_facet | Emma Lorentzon Istvan Horvath Ranjeet Kumar Joana Isabel Rodrigues Markus J. Tamás Pernilla Wittung-Stafshede |
| author_sort | Emma Lorentzon |
| collection | DOAJ |
| description | 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 <i>Saccharomyces cerevisiae</i> (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. |
| first_indexed | 2024-03-10T06:02:50Z |
| format | Article |
| id | doaj.art-93304e0595a04fb29a3e1ab124338036 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:02:50Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-93304e0595a04fb29a3e1ab1243380362023-11-22T20:52:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211145510.3390/ijms222111455Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in CellsEmma Lorentzon0Istvan Horvath1Ranjeet Kumar2Joana Isabel Rodrigues3Markus J. Tamás4Pernilla Wittung-Stafshede5Department of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, SwedenDepartment of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, SwedenDepartment of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, SwedenDepartment of Chemistry and Molecular Biology, University of Gothenburg, SE-405 30 Gothenburg, SwedenDepartment of Biology and Biological Engineering, Chalmers University of Technology, SE-412 96 Gothenburg, SwedenExposure 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 <i>Saccharomyces cerevisiae</i> (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.https://www.mdpi.com/1422-0067/22/21/11455α-synucleinamyloid formationParkinson’s diseasearsenic toxicitycadmium toxicity |
| spellingShingle | Emma Lorentzon Istvan Horvath Ranjeet Kumar Joana Isabel Rodrigues Markus J. Tamás Pernilla Wittung-Stafshede Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells International Journal of Molecular Sciences α-synuclein amyloid formation Parkinson’s disease arsenic toxicity cadmium toxicity |
| title | Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells |
| title_full | Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells |
| title_fullStr | Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells |
| title_full_unstemmed | Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells |
| title_short | Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells |
| title_sort | effects of the toxic metals arsenite and cadmium on α synuclein aggregation in vitro and in cells |
| topic | α-synuclein amyloid formation Parkinson’s disease arsenic toxicity cadmium toxicity |
| url | https://www.mdpi.com/1422-0067/22/21/11455 |
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