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

• Published in: Neurobiology of disease Vol. 130; p. 104516
• Main Authors: Hashiguchi, Shunta, Doi, Hiroshi, Kunii, Misako, Nakamura, Yukihiro, Shimuta, Misa, Suzuki, Etsuko, Koyano, Shigeru, Okubo, Masaki, Kishida, Hitaru, Shiina, Masaaki, Ogata, Kazuhiro, Hirashima, Fumiko, Inoue, Yukichi, Kubota, Shun, Hayashi, Noriko, Nakamura, Haruko, Takahashi, Keita, Katsumoto, Atsuko, Tada, Mikiko, Tanaka, Kenichi, Sasaoka, Toshikuni, Miyatake, Satoko, Miyake, Noriko, Saitsu, Hirotomo, Sato, Nozomu, Ozaki, Kokoro, Ohta, Kiyobumi, Yokota, Takanori, Mizusawa, Hidehiro, Mitsui, Jun, Ishiura, Hiroyuki, Yoshimura, Jun, Morishita, Shinichi, Tsuji, Shoji, Takeuchi, Hideyuki, Ishikawa, Kinya, Matsumoto, Naomichi, Ishikawa, Taro, Tanaka, Fumiaki
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01.10.2019; Elsevier
• Subjects: CACNA1G; Cerebellum; Electrophysiology; Inferior olivary nucleus; Knock-in mouse; Neurodegeneration; Purkinje cell; Spinocerebellar ataxia 42; Cerebellum; CF; Electrophysiology; ION; ACSF; pNF-H; Ub; DCN; CACNA1G; Inferior olivary nucleus; GFAP; SCA; Spinocerebellar ataxia 42; Knock-in mouse; PC; Neurodegeneration; PF; Purkinje cell; EPSC; LTD; SR
• DOI: 10.1016/j.nbd.2019.104516
• ISSN: 0969-9961

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. •The first model mouse of SCA42 with a missense mutation in Cacna1g is reported.•The model mice recapitulated a young adult-onset ataxic phenotype.•Purkinje cell degeneration was pathologically confirmed in aged mice.•Aberrant channel activities were found in Purkinje cells and olivary neurons.