Transgenic rat model of Huntington's disease

• Published in: Human molecular genetics 2003-03, Vol.12 (6), p.617-624
• Main Authors: von Hörsten, Stephan, Schmitt, Ina, Nguyen, Huu Phuc, Holzmann, Carsten, Schmidt, Thorsten, Walther, Thomas, Bader, Michael, Pabst, Reinhard, Kobbe, Philipp, Krotova, Jana, Stiller, Detlef, Kask, Ants, Vaarmann, Annika, Rathke-Hartlieb, Silvia, Schulz, Jörg B., Grasshoff, Ute, Bauer, Ingrid, Vieira-Saecker, Ana Maria Menezes, Paul, Martin, Jones, Lesley, Lindenberg, Katrin S., Landwehrmeyer, Bernhard, Bauer, Andreas, Li, Xiao-Jiang, Riess, Olaf
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Biological and medical sciences; Cell Nucleus - metabolism; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Disease Progression; DNA, Complementary - metabolism; Glucose - metabolism; Huntingtin Protein; Huntington Disease - genetics; Huntington Disease - pathology; Immunohistochemistry; Magnetic Resonance Imaging; Medical sciences; Models, Genetic; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurology; Neurons - metabolism; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Phenotype; Promoter Regions, Genetic; Rats; Time Factors; Tissue Distribution; Tomography, Emission-Computed; Transgenes; Trinucleotide Repeat Expansion; Tryptophan - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddg075

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.