TY - JOUR T1 - Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease JF - The Journal of Neuroscience JO - J. Neurosci. SP - 2471 LP - 2484 DO - 10.1523/JNEUROSCI.3040-07.2008 VL - 28 IS - 10 AU - Silke Nuber AU - Elisabeth Petrasch-Parwez AU - Beate Winner AU - Jürgen Winkler AU - Stephan von Hörsten AU - Thorsten Schmidt AU - Jana Boy AU - Melanie Kuhn AU - Huu P. Nguyen AU - Peter Teismann AU - Jörg B. Schulz AU - Manuela Neumann AU - Bernd J. Pichler AU - Gerald Reischl AU - Carsten Holzmann AU - Ina Schmitt AU - Antje Bornemann AU - Wilfried Kuhn AU - Frank Zimmermann AU - Antonio Servadio AU - Olaf Riess Y1 - 2008/03/05 UR - http://www.jneurosci.org/content/28/10/2471.abstract N2 - α-Synuclein (α-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 α-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 α-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 α-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, α-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model. ER -