Neurobiology of Disease (Oct 2019)

Ataxic phenotype with altered CaV3.1 channel property in a mouse model for spinocerebellar ataxia 42

  • Shunta Hashiguchi,
  • Hiroshi Doi,
  • Misako Kunii,
  • Yukihiro Nakamura,
  • Misa Shimuta,
  • Etsuko Suzuki,
  • Shigeru Koyano,
  • Masaki Okubo,
  • Hitaru Kishida,
  • Masaaki Shiina,
  • Kazuhiro Ogata,
  • Fumiko Hirashima,
  • Yukichi Inoue,
  • Shun Kubota,
  • Noriko Hayashi,
  • Haruko Nakamura,
  • Keita Takahashi,
  • Atsuko Katsumoto,
  • Mikiko Tada,
  • Kenichi Tanaka,
  • Toshikuni Sasaoka,
  • Satoko Miyatake,
  • Noriko Miyake,
  • Hirotomo Saitsu,
  • Nozomu Sato,
  • Kokoro Ozaki,
  • Kiyobumi Ohta,
  • Takanori Yokota,
  • Hidehiro Mizusawa,
  • Jun Mitsui,
  • Hiroyuki Ishiura,
  • Jun Yoshimura,
  • Shinichi Morishita,
  • Shoji Tsuji,
  • Hideyuki Takeuchi,
  • Kinya Ishikawa,
  • Naomichi Matsumoto,
  • Taro Ishikawa,
  • Fumiaki Tanaka

Journal volume & issue
Vol. 130
p. 104516

Abstract

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Spinocerebellar ataxia 42 (SCA42) is a neurodegenerative disorder recently shown to be caused by c.5144G > A (p.Arg1715His) mutation in CACNA1G, which encodes the T-type voltage-gated calcium channel CaV3.1. Here, we describe a large Japanese family with SCA42. Postmortem pathological examination revealed severe cerebellar degeneration with prominent Purkinje cell loss without ubiquitin accumulation in an SCA42 patient. To determine whether this mutation causes ataxic symptoms and neurodegeneration, we generated knock-in mice harboring c.5168G > A (p.Arg1723His) mutation in Cacna1g, corresponding to the mutation identified in the SCA42 family. Both heterozygous and homozygous mutants developed an ataxic phenotype from the age of 11–20 weeks and showed Purkinje cell loss at 50 weeks old. Degenerative change of Purkinje cells and atrophic thinning of the molecular layer were conspicuous in homozygous knock-in mice. Electrophysiological analysis of Purkinje cells using acute cerebellar slices from young mice showed that the point mutation altered the voltage dependence of CaV3.1 channel activation and reduced the rebound action potentials after hyperpolarization, although it did not significantly affect the basic properties of synaptic transmission onto Purkinje cells. Finally, we revealed that the resonance of membrane potential of neurons in the inferior olivary nucleus was decreased in knock-in mice, which indicates that p.Arg1723His CaV3.1 mutation affects climbing fiber signaling to Purkinje cells. Altogether, our study shows not only that a point mutation in CACNA1G causes an ataxic phenotype and Purkinje cell degeneration in a mouse model, but also that the electrophysiological abnormalities at an early stage of SCA42 precede Purkinje cell loss.

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