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The bacterial amyloids phenol soluble modulins from staphylococcus aureus catalyze alpha-synuclein aggregation

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  • Caroline Haikal, Lund University
  • ,
  • Lei Ortigosa Pascual, Lund University
  • ,
  • Zahra Najarzadeh
  • ,
  • Katja Bernfur, Lund University
  • ,
  • Alexander Svanbergsson, Lund University
  • ,
  • Daniel E. Otzen
  • Sara Linse, Lund University
  • ,
  • Jia Yi Li, Lund University, China Medical University

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. Staphylococcus aureus is a bacterium carried by 30–70% of the general population. It has been shown to produce functional amy-loids, 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.

TidsskriftInternational Journal of Molecular Sciences
StatusUdgivet - nov. 2021

Bibliografisk note

Funding Information:
Funding: We acknowledge financial supports by The Swedish Research Council (K2015-61X-22297-03-4; 2019-01551; 2015-00143), EU-JPND research (aSynProtec and REfrAME) and EU-Horizon2020 (MSCA-ITN-2016, SynDeGen), ParkinsonFonden, the Strategic Research Area Multipark (Multidisciplinary research in Parkinson’s disease at Lund University) and the National Natural Science Foundation of China (81430025, 31800898, and U1801681) and the Key Field Research Development Program of Guangdong Province (2018B030337001). D. E. O. is supported by the Innovation Foundation Denmark (Grant 5188-00003B) through the Joint Programme on Neurodegenerative Diseases (aSynProtec) and the Independent Research Foundation Denmark| Technical Sciences (grant no. 6111-00241B).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

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