Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice.

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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 Q 129 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 Q 76 and Q 129 transgenes were each 80 % of that of the endogenous mouse gene , whereas only the Q 129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile -onset DRPLA patients . Electrophysiological studies of the Q 129 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 alpha-amino-3 -hydroxy-5 -methyl-4 -isoxazolepropionic acid and gamma-aminobutyrate type A receptors in CA 1 neurons were also observed . Neuropathological studies of the Q 129 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 Q 76 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 Q 129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions .