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

Silke Nuber, Thomas Franck, Hartwig Wolburg, Ulrike Schumann, Nicolas Casadei, Kristina Fischer, Carsten Calaminus, Bernd J Pichler, Sittinan Chanarat, Peter Teismann, Jörg B Schulz, Andreas R Luft, Jürgen Tomiuk, Johannes Wilbertz, Antje Bornemann, Rejko Krüger, Olaf Riess

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 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.
Original languageEnglish
Pages (from-to)107-120
Number of pages14
JournalNeurogenetics
Volume11
Issue number1
Early online date17 Sep 2009
DOIs
Publication statusPublished - 1 Feb 2010

Keywords

  • animals
  • brain
  • carrier proteins
  • female
  • humans
  • immunohistochemistry
  • male
  • mice
  • mice, transgenic
  • microscopy, electron
  • models, genetic
  • nerve tissue proteins
  • neurotransmitter agents
  • positron-emission tomography
  • Purkinje cells
  • transgenes
  • alpha-synuclein
  • synphilin-1
  • R621C
  • mouse model
  • Parkinson’s disease
  • dark
  • cell degeneration
  • Purkinje cell
  • alpha-synucleinopathies
  • neurotransmitter

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    Nuber, S., Franck, T., Wolburg, H., Schumann, U., Casadei, N., Fischer, K., Calaminus, C., Pichler, B. J., Chanarat, S., Teismann, P., Schulz, J. B., Luft, A. R., Tomiuk, J., Wilbertz, J., Bornemann, A., Krüger, R., & Riess, O. (2010). Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. Neurogenetics, 11(1), 107-120. https://doi.org/10.1007/s10048-009-0212-2