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

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alpha-Synuclein
Parkinson Disease
Transgenic Mice
Lewy Bodies
Proteins
Motor Skills
Purkinje Cells
Ubiquitin
Dopamine
Cell Death
Learning

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

Cite this

Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. / Nuber, Silke; Franck, Thomas; Wolburg, Hartwig; Schumann, Ulrike; Casadei, Nicolas; Fischer, Kristina; Calaminus, Carsten; Pichler, Bernd J; Chanarat, Sittinan; Teismann, Peter; Schulz, Jörg B; Luft, Andreas R; Tomiuk, Jürgen; Wilbertz, Johannes; Bornemann, Antje; Krüger, Rejko; Riess, Olaf.

In: Neurogenetics, Vol. 11, No. 1, 01.02.2010, p. 107-120.

Research output: Contribution to journalArticle

Nuber, S, Franck, T, Wolburg, H, Schumann, U, Casadei, N, Fischer, K, Calaminus, C, Pichler, BJ, Chanarat, S, Teismann, P, Schulz, JB, Luft, AR, 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, vol. 11, no. 1, pp. 107-120. https://doi.org/10.1007/s10048-009-0212-2
Nuber, Silke ; Franck, Thomas ; Wolburg, Hartwig ; Schumann, Ulrike ; Casadei, Nicolas ; Fischer, Kristina ; Calaminus, Carsten ; Pichler, Bernd J ; Chanarat, Sittinan ; Teismann, Peter ; Schulz, Jörg B ; Luft, Andreas R ; Tomiuk, Jürgen ; Wilbertz, Johannes ; Bornemann, Antje ; Krüger, Rejko ; Riess, Olaf. / Transgenic overexpression of the alpha-synuclein interacting protein synphilin-1 leads to behavioral and neuropathological alterations in mice. In: Neurogenetics. 2010 ; Vol. 11, No. 1. pp. 107-120.
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AU - Casadei, Nicolas

AU - Fischer, Kristina

AU - Calaminus, Carsten

AU - Pichler, Bernd J

AU - Chanarat, Sittinan

AU - Teismann, Peter

AU - Schulz, Jörg B

AU - Luft, Andreas R

AU - Tomiuk, Jürgen

AU - Wilbertz, Johannes

AU - Bornemann, Antje

AU - Krüger, Rejko

AU - Riess, Olaf

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N2 - 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.

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