Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease

Silke Nuber, Elisabeth Petrasch-Parwez, Beate Winner, Jürgen Winkler, Stephan von Hörsten, Thorsten Schmidt, Jana Boy, Melanie Kuhn, Huu P. Nguyen, Peter Teismann, Jörg B Schulz, Manuela Neumann, Bernd J Pichler, Gerald Reischl, Carsten Holzmann, Ina Schmitt, Antje Bornemann, Wilfried Kuhn, Frank Zimmermann, Antonio ServadioOlaf Riess

Research output: Contribution to journalArticle

125 Citations (Scopus)

Abstract

Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.
Original languageEnglish
Pages (from-to)2471-2484
Number of pages14
JournalJournal of Neuroscience
Volume28
Issue number10
DOIs
Publication statusPublished - 5 Mar 2008

Keywords

  • animals
  • cricetinae
  • disease models, animal
  • effect modifiers (epidemiology)
  • humans
  • mice
  • mice, inbred C57BL
  • mice, transgenic
  • motor skills disorders
  • nerve degeneration
  • Parkinson disease
  • conditional
  • -synuclein
  • neurodegeneration
  • Parkinson's disease
  • mouse model
  • dark cells

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    Nuber, S., Petrasch-Parwez, E., Winner, B., Winkler, J., von Hörsten, S., Schmidt, T., Boy, J., Kuhn, M., Nguyen, H. P., Teismann, P., Schulz, J. B., Neumann, M., Pichler, B. J., Reischl, G., Holzmann, C., Schmitt, I., Bornemann, A., Kuhn, W., Zimmermann, F., ... Riess, O. (2008). Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease. Journal of Neuroscience, 28(10), 2471-2484. https://doi.org/10.1523/JNEUROSCI.3040-07.2008