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Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice

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Abstract

Synphilin-1 has been identified as an interacting protein of alpha-synuclein, Parkin, and LRRK2, proteins which are mutated in familial forms of Parkinson’s disease (PD). Subsequently, synphilin-1 has also been shown to be an intrinsic component of Lewy bodies in sporadic PD. In order to elucidate the role of synphilin-1 in the pathogenesis of PD, we generated transgenic mice overexpressing wild-type and mutant (R621C) synphilin-1 driven by a mouse prion protein promoter. Transgenic expression of both wild-type and the R621C variant synphilin-1 resulted in increased dopamine levels of the nigrostriatal system in 3-month-old mice. Furthermore, we found pathological ubiquitin-positive inclusions in cerebellar sections and dark-cell degeneration of Purkinje cells. Both transgenic mouse lines showed significant reduction of motor skill learning and motor performance. These findings suggest a pathological role of overexpressed synphilin-1 in vivo and will help to further elucidate the mechanisms of protein aggregation and neuronal cell death.

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Acknowledgement

We thank our colleagues for the fruitful discussion; in particular, Simone Engelender, Philipp Kahle, and Elisabeth Petrasch-Parwez. We would like to thank Jana Boy and Thorsten Schmidt for the kind assistance with the qPCR. The technical help with electron microscopy by Gabi Frommer-Kästle was greatly appreciated. This study was supported by a National Genome Research Network (NGFN) research grant (01GS0468) to O. Riess.

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Authors and Affiliations

  1. Department of Medical Genetics, University of Tübingen, Calwerstr. 7, 72076, Tübingen, Germany

    Silke Nuber, Thomas Franck, Ulrike Schumann, Nicolas Casadei, Jürgen Tomiuk & Olaf Riess

  2. Department of Pathology, University of Tübingen, Tübingen, Germany

    Hartwig Wolburg

  3. Laboratory for Preclinical Imaging of the Werner Siemens-Foundation, Department of Radiology, University of Tübingen, Tübingen, Germany

    Kristina Fischer, Carsten Calaminus & Bernd J. Pichler

  4. Department of Chemistry and Biochemistry, University of Munich, Munich, Germany

    Sittinan Chanarat

  5. Institute of Medical Sciences, University of Aberdeen, Aberdeen, Scotland

    Peter Teismann

  6. Department of Neurology, RWTH Aachen, Aachen, Germany

    Jörg B. Schulz

  7. Department of Neurology, Clinical Neurorehabilitation, Zürich, Switzerland

    Andreas R. Luft

  8. Karolinska Institute, University of Stockholm, Stockholm, Sweden

    Johannes Wilbertz

  9. Institute of Brain Research, University of Tübingen, Tübingen, Germany

    Antje Bornemann

  10. Center of Neurology, Hertie-Institute for Clinical Brain Research, Tübingen, Germany

    Rejko Krüger

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  1. Silke Nuber
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Correspondence to Olaf Riess.

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Silke Nuber and Thomas Franck contributed equally to this work.

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Suppl. Fig. 1

Altered glucose metabolism in synphilin-1 transgenic mice. a [18F]FDG uptake measured as standard uptake volume (SUV) of various brain areas and of muscle tissue of the right and left forepaw. The graphs display from left to right the bulbus olfactorius, cerebellum, striatum, and the muscle of transgenic (WT and R621C) synphilin-1 mice compared to control mice, displaying upregulated global glucose metabolism. There is no significant difference between transgenic and control mice in the SUV of muscle tissue. b [18F]FDG uptake expressed as ratio of SUV of various brain areas to SUV of muscle tissue of the right and left forepaw. There was no significance detected in [18F]FDG uptake ratios between the tested groups. The graphs display from left to right the bulbus olfactorius/muscle, cerebellum/muscle, and striatum/muscle ratio. Error bars represent the standard deviation of each group and black stars indicate significant difference (t test; p < 0.05). (GIF 86 kb)

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Nuber, S., Franck, T., Wolburg, H. et al. Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. Neurogenetics 11, 107–120 (2010). https://doi.org/10.1007/s10048-009-0212-2

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  • DOI: https://doi.org/10.1007/s10048-009-0212-2

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