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The Journal of Neuroscience, March 5, 2008, 28(10):2471-2484; doi:10.1523/JNEUROSCI.3040-07.2008

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Neurobiology of Disease
Neurodegeneration and Motor Dysfunction in a Conditional Model of Parkinson's Disease

Silke Nuber,¹ Elisabeth Petrasch-Parwez,⁵ Beate Winner,⁶ Jürgen Winkler,⁶ Stephan von Hörsten,⁷ Thorsten Schmidt,¹ Jana Boy,¹ Melanie Kuhn,¹ Huu P. Nguyen,¹ Peter Teismann,⁸ Jörg B. Schulz,⁹ Manuela Neumann,¹⁰ Bernd J. Pichler,³ Gerald Reischl,² Carsten Holzmann,¹¹ Ina Schmitt,¹² Antje Bornemann,⁴ Wilfried Kuhn,¹³ Frank Zimmermann,¹⁴ Antonio Servadio,¹⁵ and Olaf Riess¹

Departments of ¹Medical Genetics and ²Radiology, ³Radiopharmacy, PET Center, and ⁴Institute of Brain Research, University of Tuebingen, D-72076 Tuebingen, Germany, ⁵Institute of Neuroanatomy and Molecular Brain Research, University of Bochum, D-44780 Bochum, Germany, ⁶Department of Neurology, University of Regensburg, D-93053 Regensburg, Germany, ⁷Department of Experimental Therapy, University of Erlangen, D-91054 Erlangen, Germany, ⁸Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, United Kingdom, ⁹Department of Neurodegeneration and Restorative Research, Center of Molecular Physiology of the Brain, University of Goettingen, D-37073 Goettingen, Germany, ¹⁰Center for Neuropathology and Prion Research, Ludwigs Maximilians University, D-81377 Munich, Germany, ¹¹Department of Human Genetics, University of Rostock, D-18055 Rostock, Germany, ¹²Clinic for Neurology, University of Bonn, D-53105 Bonn, Germany, ¹³Leopoldina Hospital of Neurology, D-97422 Schweinfurt, Germany, ¹⁴Center for Molecular Biology, University of Heidelberg, 69120 Heidelberg, Germany, and ¹⁵Telethon Institute of Genetics and Medicine, 80131 Naples, Italy

Correspondence should be addressed to Olaf Riess, Department of Medical Genetics, University of Tuebingen, Calwerstrasse 7, D-72076 Tuebingen, Germany. Email: olaf.riess{at}med.uni-tuebingen.de

-Synuclein (-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 -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 -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 -syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, -syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model.

Key words: conditional; -synuclein; neurodegeneration; Parkinson's disease; mouse model; dark cells

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Received July 4, 2007; revised Jan. 11, 2008; accepted Jan. 19, 2008.

Correspondence should be addressed to Olaf Riess, Department of Medical Genetics, University of Tuebingen, Calwerstrasse 7, D-72076 Tuebingen, Germany. Email: olaf.riess{at}med.uni-tuebingen.de

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