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AAV2/DJ-mediated alpha-synuclein overexpression in the rat substantia nigra as early stage model of Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is pathologically characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and alpha-synucleinopathy. We mimic the disease pathology with overexpression of either the human α-syn wildtype (α-syn-WT) or E46K mutant form (α-syn-E46K) in DA neurons of the SNpc in adult rats using AAV2/DJ as a viral vector for the first time. Transduction efficiency was compared to an equal virus titer expressing the green fluorescent protein (GFP). Motor skills of all animals were evaluated in the cylinder and amphetamine-induced rotation test over a total time period of 12 weeks. Additionally, stereological quantification of DA cells and striatal fiber density measurements were performed every 4 weeks after injection. Rats overexpressing α-syn-WT showed a progressive loss of DA neurons with 40% reduction after 12 weeks accompanied by a greater loss of striatal DA fibers. In contrast, α-syn-E46K led to this reduction after 4 weeks without further progress. Insoluble α-syn positive cytoplasmic inclusions were observed in both groups within DA neurons of the SNpc and VTA. In addition, both α-syn groups developed a characteristic worsening of the rotational behavior over time. However, only the α-syn-WT group reached statistically significant different values in the cylinder test. Summarizing these effects, we established a motor symptom animal model of PD by using AAV2/DJ in the brain for the first time. Thereby, overexpressing of α-syn-E46K mimicked a rather pre-symptomatic stage of the disease, while the α-syn-WT overexpressing animals imitated an early symptomatic stage of PD.

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Acknowledgements

We thank Hella Brinkmann, Silke Fischer, Natascha Heidrich, Kerstin Kuhlemann and Maike Wesemann (Institute of Neuroanatomy and Cell Biology) for excellent technical assistance.

Funding

This work was financially supported by the Konrad-Adenauer-Stiftung (Friederike Freiin von Hövel).

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  1. Friederike Freiin von Hövel and Regina Rumpel contributed equally to this work.

Authors and Affiliations

  1. Institute of Neuroanatomy and Cell Biology, Hannover Medical School, OE 4140, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Friederike Freiin von Hövel, Andreas Ratzka, Dietmar Schreiner & Claudia Grothe

  2. Center for Systems Neuroscience (ZSN), Hannover Medical School, Institute of Neuroanatomy and Cell Biology, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Friederike Freiin von Hövel, Dietmar Schreiner & Claudia Grothe

  3. Institute for Laboratory Animal Science and Central Animal Facility, Hannover Medical School, OE 8600, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Regina Rumpel

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  1. Friederike Freiin von Hövel
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von Hövel, F.F., Rumpel, R., Ratzka, A. et al. AAV2/DJ-mediated alpha-synuclein overexpression in the rat substantia nigra as early stage model of Parkinson’s disease. Cell Tissue Res 378, 1–14 (2019). https://doi.org/10.1007/s00441-019-03013-x

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