The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation

Aggregated α-synuclein (α-syn) is the main constituent of Lewy bodies, which are a pathological hallmark of Parkinson’s disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric α-syn. Braak’s seminal work redirected att...

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Autores principales:	Caroline Haikal, Lei Ortigosa-Pascual, Zahra Najarzadeh, Katja Bernfur, Alexander Svanbergsson, Daniel E. Otzen, Sara Linse, Jia-Yi Li
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	alpha-synuclein bacterial amyloids aggregation protein folding Parkinson’s disease Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/b072e9c3bf4a426095235a963191db7f
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spelling	oai:doaj.org-article:b072e9c3bf4a426095235a963191db7f2021-11-11T17:04:28ZThe Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation10.3390/ijms2221115941422-00671661-6596https://doaj.org/article/b072e9c3bf4a426095235a963191db7f2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11594https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Aggregated α-synuclein (α-syn) is the main constituent of Lewy bodies, which are a pathological hallmark of Parkinson’s disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric α-syn. Braak’s seminal work redirected attention to the intestine and recent reports of dysbiosis have highlighted the potential causative role of the microbiome in the initiation of pathology of PD. <i>Staphylococcus aureus</i> is a bacterium carried by 30–70% of the general population. It has been shown to produce functional amyloids, called phenol soluble modulins (PSMαs). Here, we studied the kinetics of α-syn aggregation under quiescent conditions in the presence or absence of four different PSMα peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure α-syn monomer did not aggregate up to 450 h after initiation of the experiment in neither neutral nor mildly acidic buffer, the addition of different PSMα peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSMα peptides displayed distinct effects on the kinetics of α-syn aggregation. Kinetic analyses of the data suggest that all four peptides catalyze α-syn aggregation through heterogeneous primary nucleation. The immunogold electron microscopic analyses showed that the aggregates were fibrillar and composed of α-syn. In addition of the co-aggregated materials to a cell model expressing the A53T α-syn variant fused to GFP was found to catalyze α-syn aggregation and phosphorylation in the cells. Our results provide evidence of a potential trigger of synucleinopathies and could have implications for the prevention of the diseases.Caroline HaikalLei Ortigosa-PascualZahra NajarzadehKatja BernfurAlexander SvanbergssonDaniel E. OtzenSara LinseJia-Yi LiMDPI AGarticlealpha-synucleinbacterial amyloidsaggregationprotein foldingParkinson’s diseaseBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11594, p 11594 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	alpha-synuclein bacterial amyloids aggregation protein folding Parkinson’s disease Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	alpha-synuclein bacterial amyloids aggregation protein folding Parkinson’s disease Biology (General) QH301-705.5 Chemistry QD1-999 Caroline Haikal Lei Ortigosa-Pascual Zahra Najarzadeh Katja Bernfur Alexander Svanbergsson Daniel E. Otzen Sara Linse Jia-Yi Li The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
description	Aggregated α-synuclein (α-syn) is the main constituent of Lewy bodies, which are a pathological hallmark of Parkinson’s disease (PD). Environmental factors are thought to be potential triggers capable of initiating the aggregation of the otherwise monomeric α-syn. Braak’s seminal work redirected attention to the intestine and recent reports of dysbiosis have highlighted the potential causative role of the microbiome in the initiation of pathology of PD. <i>Staphylococcus aureus</i> is a bacterium carried by 30–70% of the general population. It has been shown to produce functional amyloids, called phenol soluble modulins (PSMαs). Here, we studied the kinetics of α-syn aggregation under quiescent conditions in the presence or absence of four different PSMα peptides and observed a remarkable shortening of the lag phase in their presence. Whereas pure α-syn monomer did not aggregate up to 450 h after initiation of the experiment in neither neutral nor mildly acidic buffer, the addition of different PSMα peptides resulted in an almost immediate increase in the Thioflavin T (ThT) fluorescence. Despite similar peptide sequences, the different PSMα peptides displayed distinct effects on the kinetics of α-syn aggregation. Kinetic analyses of the data suggest that all four peptides catalyze α-syn aggregation through heterogeneous primary nucleation. The immunogold electron microscopic analyses showed that the aggregates were fibrillar and composed of α-syn. In addition of the co-aggregated materials to a cell model expressing the A53T α-syn variant fused to GFP was found to catalyze α-syn aggregation and phosphorylation in the cells. Our results provide evidence of a potential trigger of synucleinopathies and could have implications for the prevention of the diseases.
format	article
author	Caroline Haikal Lei Ortigosa-Pascual Zahra Najarzadeh Katja Bernfur Alexander Svanbergsson Daniel E. Otzen Sara Linse Jia-Yi Li
author_facet	Caroline Haikal Lei Ortigosa-Pascual Zahra Najarzadeh Katja Bernfur Alexander Svanbergsson Daniel E. Otzen Sara Linse Jia-Yi Li
author_sort	Caroline Haikal
title	The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
title_short	The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
title_full	The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
title_fullStr	The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
title_full_unstemmed	The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation
title_sort	bacterial amyloids phenol soluble modulins from <i>staphylococcus aureus</i> catalyze alpha-synuclein aggregation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/b072e9c3bf4a426095235a963191db7f
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The Bacterial Amyloids Phenol Soluble Modulins from <i>Staphylococcus aureus</i> Catalyze Alpha-Synuclein Aggregation

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