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Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates

View ORCID ProfileSara Elfarrash, Nanna Møller Jensen, Nelson Ferreira, View ORCID ProfileCristine Betzer, Jervis Vermal Thevathasan, Robin Diekmann, Mohamed Adel, Nisreen Mansour Omar, Mohamed Z. Boraie, Sabry Gad, Jonas Ries, Deniz Kirik, Sadegh Nabavi, View ORCID ProfilePoul Henning Jensen
doi: https://doi.org/10.1101/681064
Sara Elfarrash
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
2Department of Biomedicine, Aarhus University, Aarhus, Denmark
3Department of Medical Physiology, Mansoura University, Egypt
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Nanna Møller Jensen
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
2Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Nelson Ferreira
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
2Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Cristine Betzer
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
2Department of Biomedicine, Aarhus University, Aarhus, Denmark
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Jervis Vermal Thevathasan
4European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany
5Collaboration for joint PhD degree between EMBL and Heidelberg University, Faculty of Biosciences
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Robin Diekmann
4European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany
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Mohamed Adel
3Department of Medical Physiology, Mansoura University, Egypt
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Nisreen Mansour Omar
3Department of Medical Physiology, Mansoura University, Egypt
6Fakeeh college of Biomedical Sciences, KSA
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Mohamed Z. Boraie
3Department of Medical Physiology, Mansoura University, Egypt
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Sabry Gad
3Department of Medical Physiology, Mansoura University, Egypt
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Jonas Ries
4European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, Heidelberg, Germany
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Deniz Kirik
7Brain Repair and Imaging in Neural Systems (BRAINS) Unit, Department of Experimental Medical Science, Lund University, Lund, Sweden
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Sadegh Nabavi
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
8Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
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Poul Henning Jensen
1Danish Research Institute of Translational Neuroscience – DANDRITE, Aarhus University, Aarhus, Denmark
2Department of Biomedicine, Aarhus University, Aarhus, Denmark
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  • For correspondence: phj@biomed.au.dk
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Abstract

Here we describe the use of an organotypic hippocampal slice model for studying α-synuclein aggregation and inter-neuronal spreading initiated by injection of preformed α-synuclein filaments (PFFs). PFF injection at dentate gyrus templates the endogenous α-synuclein to form aggregates in axons and cell bodies that spread to CA3 and CA1 regions. Aggregates were insoluble and phosphorylated at serine 129, recapitulating Lewy pathology features found in Parkinson’s disease and other synucleinopathies. The spreading of the aggregates were favoring the anterograde direction in the slice model. The model allowed development of slices expressing only serine-129 phosphorylation-deficient human α-synuclein (S129G) using adeno-associated viral (AAV) vector in α-synuclein knockout slices. Processes of aggregation and spreading of α-synuclein were thereby shown to be independent of phosphorylation at serine 129. We provide methods and highlight crucial steps for PFF microinjection and characterization of aggregate formation and spreading. Slices derived from genetically engineered mice or manipulated by using viral vectors allow testing of hypotheses on mechanisms involved in formation of α-synuclein aggregates and their prion-like spreading.

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Posted June 24, 2019.
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Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates
Sara Elfarrash, Nanna Møller Jensen, Nelson Ferreira, Cristine Betzer, Jervis Vermal Thevathasan, Robin Diekmann, Mohamed Adel, Nisreen Mansour Omar, Mohamed Z. Boraie, Sabry Gad, Jonas Ries, Deniz Kirik, Sadegh Nabavi, Poul Henning Jensen
bioRxiv 681064; doi: https://doi.org/10.1101/681064
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Organotypic slice culture model demonstrates interneuronal spreading of alpha-synuclein aggregates
Sara Elfarrash, Nanna Møller Jensen, Nelson Ferreira, Cristine Betzer, Jervis Vermal Thevathasan, Robin Diekmann, Mohamed Adel, Nisreen Mansour Omar, Mohamed Z. Boraie, Sabry Gad, Jonas Ries, Deniz Kirik, Sadegh Nabavi, Poul Henning Jensen
bioRxiv 681064; doi: https://doi.org/10.1101/681064

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