α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity-Reference-Cited by-同舟云学术

α-Synuclein phosphorylation at serine 129 occurs after initial protein deposition and inhibits seeded fibril formation and toxicity

Published:2022-03-30 Issue:15 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Ghanem Simona S.¹,Majbour Nour K.¹,Vaikath Nishant N.¹^ORCID,Ardah Mustafa T.²,Erskine Daniel³,Jensen Nanna Møller⁴⁵^ORCID,Fayyad Muneera¹,Sudhakaran Indulekha P.¹^ORCID,Vasili Eftychia⁶^ORCID,Melachroinou Katerina⁷^ORCID,Abdi Ilham Y.¹^ORCID,Poggiolini Ilaria¹,Santos Patricia⁶^ORCID,Dorn Anton⁸^ORCID,Carloni Paolo⁸⁹¹⁰¹¹^ORCID,Vekrellis Kostas⁷,Attems Johannes³,McKeith Ian³^ORCID,Outeiro Tiago F.⁶¹²³,Jensen Poul Henning⁴⁵^ORCID,El-Agnaf Omar M. A.¹

Affiliation:

1. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha 34110, Qatar

2. Department of Biochemistry, College of Medicine and Health Science, United Arab Emirates University, Al Ain, United Arab Emirates

3. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne NE1 7RU, United Kingdom

4. Danish Research Institute of Translational Neuroscience, Aarhus University, 8000 Aarhus, Denmark

5. Department of Biomedicine, Aarhus University, 8000 Aarhus, Denmark

6. Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Göttingen, 37075 Göttingen, Germany

7. Center of Basic Research, Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece

8. Department of Physics, Rheinisch Westfälische Technische Aachen University, 52062 Aachen, Germany

9. Computational Biomedicine, Institute of Advanced Simulation IAS-5, 52425 Jülich, Germany

10. Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, 52425 Jülich, Germany

11. JARA Institute, Molecular Neuroscience and Imaging, Institute of Neuroscience and Medicine INM-11, Forschungszentrum Jülich GmbH, 52425 Jülich, Germany

12. Max Planck Institute for Experimental Medicine, 37075 Göttingen, Germany

Abstract

Significance Converging evidence points to the build-up of phosphorylated α-synuclein (α-syn) at residue serine 129 (pS129) in Lewy body disease, suggesting its central role in the regulation of α-syn aggregation and neuronal degeneration. However, a comprehensive understanding of the role of α-syn phosphorylation at pS129 in α-synuclenopathies pathogenesis is still lacking. Herein, we study the phosphorylation incidence and its effect on α-syn aggregation propensity and cellular toxicity. Collectively, our data suggest that pS129 occurred subsequent to initial α-syn aggregation, lessened aggregation propensity, and attenuated cytotoxicity through diverse assays. Our findings highlight major implications for a better understanding of the role of a molecular modification on protein aggregation.

Funder

Qatar Biomedical Research Institute, Internal Grant

Alzheimer&amp;apos;s Research UK Fellowship

Lundbeck Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2109617119

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