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α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading

Abstract

Recent evidence suggests that disease progression in Parkinson’s disease (PD) could occur by the spreading of α-synuclein (α-syn) aggregates between neurons. Here we studied the role of astrocytes in the intercellular transfer and fate of α-syn fibrils, using in vitro and ex vivo models. α-Syn fibrils can be transferred to neighboring cells; however, the transfer efficiency changes depending on the cell types. We found that α-syn is efficiently transferred from astrocytes to astrocytes and from neurons to astrocytes, but less efficiently from astrocytes to neurons. Interestingly, α-syn puncta are mainly found inside the lysosomal compartments of the recipient cells. However, differently from neurons, astrocytes are able to efficiently degrade fibrillar α-syn, suggesting an active role for these cells in clearing α-syn deposits. Astrocytes co-cultured with organotypic brain slices are able to take up α-syn fibrils from the slices. Altogether our data support a role for astrocytes in trapping and clearing α-syn pathological deposits in PD.

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Acknowledgements

The authors thank all lab members for discussion and Seng Zhu for assistance in image analysis. We also thank Tracy Bellande for expert technical assistance. We gratefully acknowledge the Imagopole–Citech of Institut Pasteur (Paris), as well as the France–BioImaging infrastructure network supported by the Agence Nationale de la Recherche (ANR-10–INSB–04; Investments for the Future), the Région Ile-de-France (program Domaine d’Intérêt Majeur-Malinf) for the use of the Zeiss LSM 780 Elyra PS1 microscope, and IMAGIF facility for access to Electron Microscopes. We are also grateful for the financial support of Institut Pasteur (Paris). This work was also supported by the Agence Nationale de la Recherche (ANR 16 CE 16 0019 01 NEUROTUNN) and the EC Joint Programme on Neurodegenerative Diseases (JPND-NeuTARGETs-ANR-14-JPCD-0002-02) to CZ and RM; by Equipe FRM (Fondation pour la Recherche Médicale) 2014 (DEQ 20140329557) and by a France Parkinson Grant to CZ; and by the Centre National de la Recherche Scientifique, France Parkinson (Contract 113344), Equipe FRM (Fondation pour la Recherche Médicale) 2016 (DEQ 20160334896), The Fondation de France (Contract 2015-00060936), the Fondation Simone et Cino Del Duca of the Institut de France, and a “Coup d’Elan à la Recherche Française” award from Fondation Bettencourt-Schueller to RM. FL is recipient of a Marie Skłodowska-Curie fellowship.

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Correspondence to Chiara Zurzolo.

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Loria, F., Vargas, J.Y., Bousset, L. et al. α-Synuclein transfer between neurons and astrocytes indicates that astrocytes play a role in degradation rather than in spreading. Acta Neuropathol 134, 789–808 (2017). https://doi.org/10.1007/s00401-017-1746-2

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Keywords

  • α-Synuclein
  • Intercellular spreading
  • Primary cultures
  • Organotypic cultures
  • Parkinson’s disease