Human Molecular Genetics Advance Access originally published online on November 27, 2008
Human Molecular Genetics 2009 18(4):723-736; doi:10.1093/hmg/ddn403
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Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice
1 Department of Comparative and Experimental Medicine 2 Department of Pathology 3 Department of Neurology 4 Department of Molecular Neuroscience, Brain Research Institute, Niigata University, Niigata 951-8585, Japan 5 Neural Circuits Dynamics Research Group, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo 173-0015, Japan 6 Department of Cellular Neurophysiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan 7 Department of Psychiatry 8 Department of Neurology 9 Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 10 Laboratory of Research Resources, National Institute for Longevity Sciences, Obu, Aichi 474-8522, Japan 11 Department of Anesthesiology, School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan 12 Institute of Neuroscience, National Yang-Ming University, Li-Rum Street, Taiwan 11221, Taiwan 13 National Institute for Basic Biology, Okazaki National Research Institutes, Okazaki, Aichi 444-8585, Japan 14 Department of Neurology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan
* To whom correspondence should be addressed. Tel: +81 358006542; Fax: +81 358006844; Email: tsuji{at}m.u-tokyo.ac.jp
Received August 1, 2008; Accepted November 25, 2008
We herein provide a thorough description of new transgenic mouse models for dentatorubral–pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through 
-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and 
-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions.
Present address: Department of Neuropharmacology, Graduate School of Medicine, Hokkaido University, Kita-ku, Sapporo 060-8638, Japan.
Present address: Academic Neurology Unit, The University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK.
¶ Present address: Department of Psychiatry, McLean Hospital, Harvard Medical School, Belmont, MA 02478, USA.
Present address: Department of Neurophysiology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.