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A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

Ivan Martinez-Valbuena, Naomi P. Visanji, Ain Kim, Heather H. C. Lau, Raphaella W. L. So, Sohaila Alshimemeri, Andrew Gao, Michael Seidman, Maria R. Luquin, Joel C. Watts, Anthony E. Lang, View ORCID ProfileGabor G. Kovacs
doi: https://doi.org/10.1101/2021.08.10.455800
Ivan Martinez-Valbuena
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
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Naomi P. Visanji
2Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
4Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada
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Ain Kim
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
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Heather H. C. Lau
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
5Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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Raphaella W. L. So
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
5Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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Sohaila Alshimemeri
2Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
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Andrew Gao
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
6Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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Michael Seidman
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
6Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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Maria R. Luquin
7Department of Neurology, Clinica Universidad de Navarra, Pamplona, Navarra, Spain
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Joel C. Watts
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
5Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada
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Anthony E. Lang
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
2Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
4Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada
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Gabor G. Kovacs
1Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada
2Edmond J. Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, Ontario, Canada
3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
4Krembil Brain Institute, University Health Network, Toronto, Ontario, Canada
6Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada
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  • ORCID record for Gabor G. Kovacs
  • For correspondence: gabor.kovacs@uhnresearch.ca
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Abstract

Several in vitro and in vivo findings have consistently shown that α-synuclein derived from multiple system atrophy (MSA) subjects has more seeding capacity than Parkinson’s disease-derived α-synuclein. However, reliable detection of α-synuclein derived from MSA using seeded amplification assays, such as the Real-Time Quaking-induced Conversion, has remained challenging. Here we demonstrate that the interaction of the Thioflavin T dye with α-synuclein from MSA and Parkinson’s disease patients can be modulated by the type of salt, pH, and ionic strength used to generate strain-specific reaction buffers. Employing this novel approach, we have generated a streamlined Real-Time Quaking-induced Conversion assay capable of categorizing MSA brains according to their α-synuclein seeding behavior, and to unravel a previously unrecognized heterogeneity in seeding activity between different brain regions of a given individual that goes beyond immunohistochemical observations and provide a framework for future molecular subtyping of MSA.

Competing Interest Statement

GGK holds shared patent for the 5G4 antibody. Other authors declare no competing interests.

Footnotes

  • ↵* email: gabor.kovacs{at}uhnresearch.ca

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy
Ivan Martinez-Valbuena, Naomi P. Visanji, Ain Kim, Heather H. C. Lau, Raphaella W. L. So, Sohaila Alshimemeri, Andrew Gao, Michael Seidman, Maria R. Luquin, Joel C. Watts, Anthony E. Lang, Gabor G. Kovacs
bioRxiv 2021.08.10.455800; doi: https://doi.org/10.1101/2021.08.10.455800
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A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy
Ivan Martinez-Valbuena, Naomi P. Visanji, Ain Kim, Heather H. C. Lau, Raphaella W. L. So, Sohaila Alshimemeri, Andrew Gao, Michael Seidman, Maria R. Luquin, Joel C. Watts, Anthony E. Lang, Gabor G. Kovacs
bioRxiv 2021.08.10.455800; doi: https://doi.org/10.1101/2021.08.10.455800

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