title: Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.
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.
authors.affiliation: Department of Medical Genetics, University of Tuebingen, D-72076 Tuebingen, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Nuber
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Petrasch-Parwez
authors.forename: Beate
authors.initials: B
authors.lastname: Winner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Winkler
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
authors.forename: Thorsten
authors.initials: T
authors.lastname: Schmidt
authors.forename: Jana
authors.initials: J
authors.lastname: Boy
authors.forename: Melanie
authors.initials: M
authors.lastname: Kuhn
authors.forename: Huu P
authors.initials: HP
authors.lastname: Nguyen
authors.forename: Peter
authors.initials: P
authors.lastname: Teismann
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Manuela
authors.initials: M
authors.lastname: Neumann
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.forename: Gerald
authors.initials: G
authors.lastname: Reischl
authors.forename: Carsten
authors.initials: C
authors.lastname: Holzmann
authors.forename: Ina
authors.initials: I
authors.lastname: Schmitt
authors.forename: Antje
authors.initials: A
authors.lastname: Bornemann
authors.forename: Wilfried
authors.initials: W
authors.lastname: Kuhn
authors.forename: Frank
authors.initials: F
authors.lastname: Zimmermann
authors.forename: Antonio
authors.initials: A
authors.lastname: Servadio
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
mesh_terms: D000818:Animals; D006224:Cricetinae; D004195:Disease Models, Animal; D015987:Effect Modifier, Epidemiologic; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019957:Motor Skills Disorders / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D009410:Nerve Degeneration / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*