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Human Molecular Genetics, 2003, Vol. 12, No. 6 617-624
© 2003 Oxford University Press

Transgenic rat model of Huntington's disease

Stephan von Hörsten1,*, Ina Schmitt2,{dagger}, Huu Phuc Nguyen1, Carsten Holzmann3, Thorsten Schmidt4, Thomas Walther5, Michael Bader6, Reinhard Pabst1, Philipp Kobbe1, Jana Krotova1, Detlef Stiller7, Ants Kask8, Annika Vaarmann8, Silvia Rathke-Hartlieb9, Jörg B. Schulz9, Ute Grasshoff4, Ingrid Bauer3, Ana Maria Menezes Vieira-Saecker2,{dagger}, Martin Paul10, Lesley Jones11, Katrin S. Lindenberg12, Bernhard Landwehrmeyer12, Andreas Bauer13, Xiao-Jiang Li14 and Olaf Riess4

1Department of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany, 2Department of Molecular Human Genetics, University of Bochum, Bochum, Germany, 3Department of Medical Genetics, Children's Hospital, University of Rostock, Rostock, Germany, 4Department of Medical Genetics, University of Tübingen, Tübingen, Germany, 5Department of Cardiology, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany, 6Max Delbrück Center for Molecular Medicine, Berlin-Buch, Germany, 7Department of Non-invasive Imaging, Leibniz Institute for Neurobiology, Magdeburg, Germany, 8Department of Pharmacology, University of Tartu, Tartu, Estonia, 9Department of Neurology, University of Tübingen, Tübingen, Germany, 10Institute of Pharmacology and Toxicology, University Hospital Benjamin Franklin, Free University of Berlin, Berlin, Germany, 11Institute of Medical Genetics, University of Wales, College of Medicine, Cardiff, UK, 12Department of Neurology, University of Ulm, Ulm, Germany, 13Institute of Medicine, Research Center, Jülich, Germany and 14Department of Human Genetics, Emory University School of Medicine, Atlanta, CA, USA

Received October 24, 2002; Accepted January 4, 2003

Huntington's disease (HD) is a late manifesting neurodegenerative disorder in humans caused by an expansion of a CAG trinucleotide repeat of more than 39 units in a gene of unknown function. Several mouse models have been reported which show rapid progression of a phenotype leading to death within 3–5 months (transgenic models) resembling the rare juvenile course of HD (Westphal variant) or which do not present with any symptoms (knock-in mice). Owing to the small size of the brain, mice are not suitable for repetitive in vivo imaging studies. Also, rapid progression of the disease in the transgenic models limits their usefulness for neurotransplantation. We therefore generated a rat model transgenic of HD, which carries a truncated huntingtin cDNA fragment with 51 CAG repeats under control of the native rat huntingtin promoter. This is the first transgenic rat model of a neurodegenerative disorder of the brain. These rats exhibit adult-onset neurological phenotypes with reduced anxiety, cognitive impairments, and slowly progressive motor dysfunction as well as typical histopathological alterations in the form of neuronal nuclear inclusions in the brain. As in HD patients, in vivo imaging demonstrates striatal shrinkage in magnetic resonance images and a reduced brain glucose metabolism in high-resolution fluor-deoxy-glucose positron emission tomography studies. This model allows longitudinal in vivo imaging studies and is therefore ideally suited for the evaluation of novel therapeutic approaches such as neurotransplantation.

* To whom correspondence should be addressed at: Department of Functional and Applied Anatomy, OE 4120, Hannover Medical School, Carl Neuberg Str. 1, 30625 Hannover, Germany. Tel: +49 5115322868; Fax: +49 5115328868; Email: hoersten.stephan.von{at}mh-hannover.de

{dagger} Present address: Department of Neurology, University of Bonn, Bonn, Germany.


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