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α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms

T. Torre Murazabal, A. Van der Perren, A. Coens, A. Barber Janer, S. Camacho-Garcia, N. Stefanova, R. Melki, V. Baekelandt, W. Peelaerts
doi: https://doi.org/10.1101/2020.10.16.342089
T. Torre Murazabal
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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A. Van der Perren
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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A. Coens
2Institut François Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France
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A. Barber Janer
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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S. Camacho-Garcia
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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N. Stefanova
3Division of Neurobiology, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
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R. Melki
2Institut François Jacob (MIRCen), CEA, and Laboratory of Neurodegenerative Diseases, CNRS, Fontenay-aux-Roses, France
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V. Baekelandt
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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  • For correspondence: wouter.peelaerts@kuleuven.be veerle.baekelandt@kuleuven.be
W. Peelaerts
1KU Leuven, Laboratory for Neurobiology and Gene Therapy, Department of Neurosciences, Leuven, Belgium
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  • For correspondence: wouter.peelaerts@kuleuven.be veerle.baekelandt@kuleuven.be
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Abstract

Multiple system atrophy (MSA) is a progressive neurodegenerative disease with prominent autonomic and motor features. Different disease subtypes are distinguished by their predominant parkinsonian or cerebellar signs. The pathognomonic feature of MSA is the presence of α-synuclein (αSyn) protein deposits in glial cells of the central and peripheral nervous system. It is unclear why MSA, that invariably presents with αSyn pathology, is clinically so heterogeneous, why it progresses at varying rates and how neuroinflammation affects disease progression. Recently, it was shown that different strains of αSyn can assemble in unique disease environments but also that a variety of strains might exist in the brain of MSA patients. We therefore investigated if different αSyn strains might influence MSA disease progression. To this aim, we injected two recombinant strains of αSyn in MSA transgenic mice and found that they significantly impact MSA disease progression in a strain-dependent way via oligodendroglial, neurotoxic and immune-related mechanisms. Neurodegeneration and brain atrophy were accompanied by unique microglial and astroglial responses and the recruitment of central and peripheral immune cells. The differential activation of microglial cells correlated with the structural features of αSyn strains both in vitro and in vivo. By injecting αSyn strains in MSA mice we could more closely mimic a comprehensive MSA phenotype in an experimental setting. This study therefore shows that i) MSA phenotype is governed by both the αSyn strain nature and the host environment and ii) αSyn strains can directly trigger a detrimental immune response related to disease progression in MSA.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 16, 2020.
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α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms
T. Torre Murazabal, A. Van der Perren, A. Coens, A. Barber Janer, S. Camacho-Garcia, N. Stefanova, R. Melki, V. Baekelandt, W. Peelaerts
bioRxiv 2020.10.16.342089; doi: https://doi.org/10.1101/2020.10.16.342089
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α-Synuclein strains influence multiple system atrophy via central and peripheral mechanisms
T. Torre Murazabal, A. Van der Perren, A. Coens, A. Barber Janer, S. Camacho-Garcia, N. Stefanova, R. Melki, V. Baekelandt, W. Peelaerts
bioRxiv 2020.10.16.342089; doi: https://doi.org/10.1101/2020.10.16.342089

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