Aarhus Universitets segl

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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Simona S. Ghanem, Hamad bin Khalifa University
  • ,
  • Nour K. Majbour, Hamad bin Khalifa University
  • ,
  • Nishant N. Vaikath, Hamad bin Khalifa University
  • ,
  • Mustafa T. Ardah, United Arab Emirates University
  • ,
  • Daniel Erskine, Newcastle University
  • ,
  • Nanna Møller Jensen
  • Muneera Fayyad, Hamad bin Khalifa University
  • ,
  • Indulekha P. Sudhakaran, Hamad bin Khalifa University
  • ,
  • Eftychia Vasili, University of Göttingen
  • ,
  • Katerina Melachroinou, Academy of Athens
  • ,
  • Ilham Y. Abdi, Hamad bin Khalifa University
  • ,
  • Ilaria Poggiolini, Hamad bin Khalifa University
  • ,
  • Patricia Santos, University of Göttingen
  • ,
  • Anton Dorn, RWTH Aachen University
  • ,
  • Paolo Carloni, RWTH Aachen University, Jülich Research Centre
  • ,
  • Kostas Vekrellis, Academy of Athens
  • ,
  • Johannes Attems, Newcastle University
  • ,
  • Ian McKeith, Newcastle University
  • ,
  • Tiago F. Outeiro, Newcastle University, University of Göttingen, Max Planck Institute of Experimental Medicine
  • ,
  • Poul Henning Jensen
  • Omar M.A. El-Agnaf, Hamad bin Khalifa University

α-Synuclein (α-syn) phosphorylation at serine 129 (pS129–α-syn) is substantially increased in Lewy body disease, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). However, the pathogenic relevance of pS129–α-syn remains controversial, so we sought to identify when pS129 modification occurs during α-syn aggregation and its role in initiation, progression and cellular toxicity of disease. Using diverse aggregation assays, including real-time quaking-induced conversion (RT-QuIC) on brain homogenates from PD and DLB cases, we demonstrated that pS129–α-syn inhibits α-syn fibril formation and seeded aggregation. We also identified lower seeding propensity of pS129–α-syn in cultured cells and correspondingly attenuated cellular toxicity. To build upon these findings, we developed a monoclonal antibody (4B1) specifically recognizing nonphosphorylated S129–α-syn (WT–α-syn) and noted that S129 residue is more efficiently phosphorylated when the protein is aggregated. Using this antibody, we characterized the time-course of α-syn phosphorylation in organotypic mouse hippocampal cultures and mice injected with α-syn preformed fibrils, and we observed aggregation of nonphosphorylated α-syn followed by later pS129–α-syn. Furthermore, in postmortem brain tissue from PD and DLB patients, we observed an inverse relationship between relative abundance of nonphosphorylated α-syn and disease duration. These findings suggest that pS129–α-syn occurs subsequent to initial protein aggregation and apparently inhibits further aggregation. This could possibly imply a potential protective role for pS129–α-syn, which has major implications for understanding the pathobiology of Lewy body disease and the continued use of reduced pS129–α-syn as a measure of efficacy in clinical trials.

OriginalsprogEngelsk
Artikelnummere2109617119
TidsskriftPNAS (Proceedings of the National Academy of Sciences of the United States of America)
Vol/bind119
Nummer15
ISSN0027-8424
DOI
StatusUdgivet - apr. 2022

Bibliografisk note

Funding Information:
ACKNOWLEDGMENTS. We thank Prof. Michael Schlossmacher (University of Ottawa, Canada) for providing SNCA transgenic and SNCA-null mouse brain tissues, and Dr. Giulia Rosseti (Forschungszentrum J€ulich, Germany) and Prof. Claudio Fernandez (Universidad Nacional de Rosario, Argentina) for their contributions to the modelling of the effect of S129 phosphorylation. The work conducted by the O.M.A.E.-A. laboratory was supported by the Qatar Biomedical Research Institute under Internal Grant VR98. D.E. is funded by an Alzheimer’s Research UK Fellowship (ARUK-RF2018C-005). Human brain tissue was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074), by National Institute for Health Research Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and by a grant from the Alzheimer’s Society and Alzheimer’s Research UK as part of the Brains for Dementia Research Project. P.H.J. is funded by Lundbeck Foundation Grants R223-2015-4222 and R248-2016-2518 for the Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic–European Molecular Biology Laboratory Partnership for Molecular Medicine, Aarhus University, Denmark.

Funding Information:
We thank Prof. Michael Schlossmacher (University of Ottawa, Canada) for providing SNCA transgenic and SNCA-null mouse brain tissues, and Dr. Giulia Rosseti (Forschungszentrum J?ulich, Germany) and Prof. Claudio Fernandez (Universidad Nacional de Rosario, Argentina) for their contributions to the modelling of the effect of S129 phosphorylation. The work conducted by the O.M.A.E.-A. laboratory was supported by the Qatar Biomedical Research Institute under Internal Grant VR98. D.E. is funded by an Alzheimer?s Research UK Fellowship (ARUK-RF2018C-005). Human brain tissue was provided by Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074), by National Institute for Health Research Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and by a grant from the Alzheimer?s Society and Alzheimer?s Research UK as part of the Brains for Dementia Research Project. P.H.J. is funded by Lundbeck Foundation Grants R223-2015-4222 and R248-2016-2518 for the Danish Research Institute of Translational Neuroscience (DANDRITE), Nordic?European Molecular Biology Laboratory Partnership for Molecular Medicine, Aarhus University, Denmark.

Publisher Copyright:
Copyright © 2022 the Author(s).

Se relationer på Aarhus Universitet Citationsformater

ID: 269223155