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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Autores principales:	Emma Lorentzon, Istvan Horvath, Ranjeet Kumar, Joana Isabel Rodrigues, Markus J. Tamás, Pernilla Wittung-Stafshede
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	α-synuclein amyloid formation Parkinson’s disease arsenic toxicity cadmium toxicity Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/93304e0595a04fb29a3e1ab124338036
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spelling	oai:doaj.org-article:93304e0595a04fb29a3e1ab1243380362021-11-11T16:55:03ZEffects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells10.3390/ijms2221114551422-00671661-6596https://doaj.org/article/93304e0595a04fb29a3e1ab1243380362021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11455https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Exposure 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.Emma LorentzonIstvan HorvathRanjeet KumarJoana Isabel RodriguesMarkus J. TamásPernilla Wittung-StafshedeMDPI AGarticleα-synucleinamyloid formationParkinson’s diseasearsenic toxicitycadmium toxicityBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11455, p 11455 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	α-synuclein amyloid formation Parkinson’s disease arsenic toxicity cadmium toxicity Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	α-synuclein amyloid formation Parkinson’s disease arsenic toxicity cadmium toxicity Biology (General) QH301-705.5 Chemistry QD1-999 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
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.
format	article
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
title	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_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_sort	effects of the toxic metals arsenite and cadmium on α-synuclein aggregation in vitro and in cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/93304e0595a04fb29a3e1ab124338036
work_keys_str_mv	AT emmalorentzon effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells AT istvanhorvath effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells AT ranjeetkumar effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells AT joanaisabelrodrigues effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells AT markusjtamas effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells AT pernillawittungstafshede effectsofthetoxicmetalsarseniteandcadmiumonasynucleinaggregationinvitroandincells
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Effects of the Toxic Metals Arsenite and Cadmium on α-Synuclein Aggregation In Vitro and in Cells

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