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Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo

Antonio Dominguez-Meijide, Valeria Parrales, Eftychia Vasili, Florencia González-Lizárraga, Annekatrin König, Diana F. Lázaro, Annie Lannuzel, Stéphane Haik, Elaine Del Bel, Rosana Chehín, Rita Raisman-Vozari, View ORCID ProfilePatrick P Michel, Nicolas Bizat, View ORCID ProfileTiago Fleming Outeiro
doi: https://doi.org/10.1101/2020.11.06.371229
Antonio Dominguez-Meijide
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
2Laboratory of Neuroanatomy and Experimental Neurology, Dept. of Morphological Sciences, CIMUS, IDIS, University of Santiago de Compostela, Santiago de Compostela, Spain
3Networking Research Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain
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Valeria Parrales
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
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Eftychia Vasili
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
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Florencia González-Lizárraga
5Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA)
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Annekatrin König
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
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Diana F. Lázaro
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
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Annie Lannuzel
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
6University Hospital of Pointe-à-Pitre, Neurology Department, route de Chauvel, 97139 Abymes, Guadeloupe
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Stéphane Haik
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
11AP-HP, Cellule Nationale de Référence des Maladies de Creutzfeldt-Jakob, University Hospital Pitié-Salpêtrière, Paris, F-75013, France
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Elaine Del Bel
7Department of Basic and Oral Biology, Faculty of Odontology of Ribeirão Preto, University of São Paulo (USP), Av do Café s/n, São Paulo, Brazil.
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  • For correspondence: eadelbel@usp.br
Rosana Chehín
5Instituto de Investigación en Medicina Molecular y Celular Aplicada (IMMCA) (CONICET-UNT-SIPROSA)
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Rita Raisman-Vozari
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
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Patrick P Michel
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
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Nicolas Bizat
4Paris Brain Institute, Inserm U 1127, CNRS UMR 7225, Sorbonne Université, F-75013 Paris, France
8Faculté de Pharmacie de Paris, Paris University, 4 avenue de l’Observatoire, Paris, F-75006, France
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Tiago Fleming Outeiro
1Department of Experimental Neurodegeneration, Center for Biostructural Imaging of Neurodegeneration, University Medical Center Goettingen, Goettingen, Germany
9Max Planck Institute for Experimental Medicine, Goettingen, Germany
10Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle Upon Tyne, NE2 4HH, UK
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  • ORCID record for Tiago Fleming Outeiro
  • For correspondence: touteir@gwdg.de
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Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are neurodegenerative disorders characterized by the misfolding and aggregation of alpha-synuclein (aSyn). Doxycycline, a tetracyclic antibiotic shows neuroprotective effects, initially proposed to be due to its anti-inflammatory properties. More recently, an additional mechanism by which doxycycline may exert its neuroprotective effects has been proposed as it has been shown that it inhibits amyloid aggregation. Here, we studied the effects of doxycycline on aSyn aggregation in vivo, in vitro and in a cell free system using real-time quaking induced conversion (RT-QuiC). Our results show that doxycycline decreases the number and size of aSyn aggregates in cells. In addition, doxycycline inhibits the aggregation and seeding of recombinant aSyn, and attenuates the production of mitochondrial-derived reactive oxygen species. Finally, we found doxycycline induces a cellular redistribution of the aggregates in an animal model of PD that is associated with a recovery of dopaminergic function. In summary, we provide strong evidence that doxycycline treatment may be an effective strategy against synucleinopathies.

Footnotes

  • ↵* Co-senior authors, Email: Prof. Dr. Tiago F. Outeiro, Department of Experimental Neurodegeneration, University Medical Center Goettingen, 37073 Goettingen, Germany, Telephone: +495513913545, Email: tiago.outeiro{at}med.uni-goettingen.de or Dr. Nicolas Bizat, Institut du Cerveau et de la Moelle, Hôpital de la Pitié-Saplêtrière, 47, Bd de l’Hôpital, Paris F-75013, France, Telephone: +331 5727 4388, Email: nicolas.bizat{at}icm-institute.org

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Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo
Antonio Dominguez-Meijide, Valeria Parrales, Eftychia Vasili, Florencia González-Lizárraga, Annekatrin König, Diana F. Lázaro, Annie Lannuzel, Stéphane Haik, Elaine Del Bel, Rosana Chehín, Rita Raisman-Vozari, Patrick P Michel, Nicolas Bizat, Tiago Fleming Outeiro
bioRxiv 2020.11.06.371229; doi: https://doi.org/10.1101/2020.11.06.371229
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Doxycycline inhibits α-synuclein-associated pathologies in vitro and in vivo
Antonio Dominguez-Meijide, Valeria Parrales, Eftychia Vasili, Florencia González-Lizárraga, Annekatrin König, Diana F. Lázaro, Annie Lannuzel, Stéphane Haik, Elaine Del Bel, Rosana Chehín, Rita Raisman-Vozari, Patrick P Michel, Nicolas Bizat, Tiago Fleming Outeiro
bioRxiv 2020.11.06.371229; doi: https://doi.org/10.1101/2020.11.06.371229

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