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

Toshiya Sato, Masami Miura, Mitsunori Yamada, Takayuki Yoshida, Jonathan D. Wood, Ikuru Yazawa, Masao Masuda, Takeo Suzuki, Ryong Moon Shin, Hau Jie Yau, Fu Chin Liu, Takayoshi Shimohata, Osamu Onodera, Christopher A Ross, Motoya Katsuki, Hitoshi Takahashi, Masanobu Kano, Toshihiko Aosaki, Shoji Tsuji

Research output: Contribution to journalArticle

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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-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.

Original languageEnglish (US)
Pages (from-to)723-736
Number of pages14
JournalHuman Molecular Genetics
Volume18
Issue number4
DOIs
StatePublished - 2009

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Progressive Myoclonic Epilepsy
Transgenic Mice
Phenotype
Genes
Aminobutyrates
Globus Pallidus
Purkinje Cells
Mutant Proteins
Dendrites
Transgenes
Cerebellum
Atrophy
Down-Regulation
Neurons
Messenger RNA
Acids
Brain

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

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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. / Sato, Toshiya; Miura, Masami; Yamada, Mitsunori; Yoshida, Takayuki; Wood, Jonathan D.; Yazawa, Ikuru; Masuda, Masao; Suzuki, Takeo; Shin, Ryong Moon; Yau, Hau Jie; Liu, Fu Chin; Shimohata, Takayoshi; Onodera, Osamu; Ross, Christopher A; Katsuki, Motoya; Takahashi, Hitoshi; Kano, Masanobu; Aosaki, Toshihiko; Tsuji, Shoji.

In: Human Molecular Genetics, Vol. 18, No. 4, 2009, p. 723-736.

Research output: Contribution to journalArticle

Sato, T, Miura, M, Yamada, M, Yoshida, T, Wood, JD, Yazawa, I, Masuda, M, Suzuki, T, Shin, RM, Yau, HJ, Liu, FC, Shimohata, T, Onodera, O, Ross, CA, Katsuki, M, Takahashi, H, Kano, M, Aosaki, T & Tsuji, S 2009, 'Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice', Human Molecular Genetics, vol. 18, no. 4, pp. 723-736. https://doi.org/10.1093/hmg/ddn403
Sato, Toshiya ; Miura, Masami ; Yamada, Mitsunori ; Yoshida, Takayuki ; Wood, Jonathan D. ; Yazawa, Ikuru ; Masuda, Masao ; Suzuki, Takeo ; Shin, Ryong Moon ; Yau, Hau Jie ; Liu, Fu Chin ; Shimohata, Takayoshi ; Onodera, Osamu ; Ross, Christopher A ; Katsuki, Motoya ; Takahashi, Hitoshi ; Kano, Masanobu ; Aosaki, Toshihiko ; Tsuji, Shoji. / Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice. In: Human Molecular Genetics. 2009 ; Vol. 18, No. 4. pp. 723-736.
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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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-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.",
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T1 - Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice

AU - Sato, Toshiya

AU - Miura, Masami

AU - Yamada, Mitsunori

AU - Yoshida, Takayuki

AU - Wood, Jonathan D.

AU - Yazawa, Ikuru

AU - Masuda, Masao

AU - Suzuki, Takeo

AU - Shin, Ryong Moon

AU - Yau, Hau Jie

AU - Liu, Fu Chin

AU - Shimohata, Takayoshi

AU - Onodera, Osamu

AU - Ross, Christopher A

AU - Katsuki, Motoya

AU - Takahashi, Hitoshi

AU - Kano, Masanobu

AU - Aosaki, Toshihiko

AU - Tsuji, Shoji

PY - 2009

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N2 - 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-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.

AB - 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 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-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.

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