Involvement of aspartoacylase in tremor expression in rats

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  • Nishitani Ai
    Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
  • Tanaka Miyuu
    Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
  • Shimizu Saki
    Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Japan
  • Kunisawa Naofumi
    Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Japan
  • Yokoe Mayuko
    Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan
  • Yoshida Yusaku
    Research Department for Experimental Animals, Biotechnical Center Japan SLC, Inc., Aoihigashi, Naka-ku, Hamamatsu, Shizuoka 433-8114, Japan
  • Suzuki Toshiro
    Research Department for Experimental Animals, Biotechnical Center Japan SLC, Inc., Aoihigashi, Naka-ku, Hamamatsu, Shizuoka 433-8114, Japan
  • Sakuma Tetsushi
    Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
  • Yamamoto Takashi
    Department of Mathematical and Life Sciences, Graduate School of Science, Hiroshima University, 1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526, Japan
  • Kuwamura Mitsuru
    Laboratory of Veterinary Pathology, Osaka Prefecture University, Izumisano, Osaka 598-8531, Japan
  • Takenaka Shigeo
    Laboratory of Molecular Biology, Osaka Prefecture University, Izumisano, Osaka 598-8531, Japan
  • Ohno Yukihiro
    Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki 569-1094, Japan
  • Kuramoto Takashi
    Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan

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抄録

Essential tremor (ET) is a common movement disorder with a poorly understood etiology. The TRM/Kyo mutant rat, showing spontaneous tremor, is an animal model of ET. Recently, we demonstrated that tremors in these rats emerge when two mutant loci, a missense mutation in the hyperpolarization-activated cyclic nucleotide-gated potassium channel 1 (Hcn1) and the tremor (tm) deletion, are present simultaneously. However, we did not identify which gene within the tm deletion causes tremor expression in TRM/Kyo rats. A strong candidate among the 13 genes within the tm deletion is aspartoacylase (Aspa), because some Aspa-knockout mouse strains show tremor. Here, we generated Aspa-knockout rats using transcription activator-like effector nuclease technology and produced Aspa/Hcn1 double-mutant rats by crossing Aspa-knockout rats with Hcn1-mutant rats. The Aspa-knockout rats carried nonsense mutations in exon 4; and ASPA proteins were not detectable in their brain extracts. They showed elevated levels of N-acetyl-L-aspartate (NAA) in urine and spongy vacuolation and abnormal myelination in the central nervous system, but no tremor. By contrast, Aspa/Hcn1 double-mutant rats spontaneously showed tremors resembling those in TRM/Kyo rats, and the tremor was suppressed by drugs therapeutic for ET but not for parkinsonian tremor. These findings indicated that the lack of the Aspa gene caused tremor expression in TRM/Kyo rats. Our animal model suggested that the interaction of NAA accumulation due to ASPA deficiency with an unstable neuronal membrane potential caused by HCN1 deficiency was involved in tremor development.

収録刊行物

  • Experimental Animals

    Experimental Animals 65 (3), 293-301, 2016

    公益社団法人 日本実験動物学会

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