title: Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice.
abstract: 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 alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and gamma-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.
authors.affiliation: Department of Comparative and Experimental Medicine, Brain Research Institute, Niigata University, Niigata, Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Sato
authors.forename: Masami
authors.initials: M
authors.lastname: Miura
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Yamada
authors.forename: Takayuki
authors.initials: T
authors.lastname: Yoshida
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Wood
authors.forename: Ikuru
authors.initials: I
authors.lastname: Yazawa
authors.forename: Masao
authors.initials: M
authors.lastname: Masuda
authors.forename: Takeo
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ryong-Moon
authors.initials: RM
authors.lastname: Shin
authors.forename: Hau-Jie
authors.initials: HJ
authors.lastname: Yau
authors.forename: Fu-Chin
authors.initials: FC
authors.lastname: Liu
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Shimohata
authors.forename: Osamu
authors.initials: O
authors.lastname: Onodera
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Motoya
authors.initials: M
authors.lastname: Katsuki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Aosaki
authors.forename: Shoji
authors.initials: S
authors.lastname: Tsuji
mesh_terms: D000367:Age Factors; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D009435:Synaptic Transmission; D019680:Trinucleotide Repeat Expansion
chemical_list: D009419:Nerve Tissue Proteins; C095278:atrophin-1