Ataxic phenotype with altered Cav3.1 channel property in a mouse model for spinocerebellar ataxia 42
Ataxic phenotype with altered Cav3.1 channel property in a mouse model for spinocerebellar ataxia 42
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DOI：
10.1016/j.nbd.2019.104516
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发表时间：
2019-10-01
影响因子：
6.1
通讯作者：
Tanaka, Fumiaki
中科院分区：
文献类型：
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作者：
Hashiguchi, Shunta;Doi, Hiroshi;Tanaka, Fumiaki
脊髓小脑性共济失调42 （SCA42）是一种神经退行性疾病，最近被证明是由编码t型电压门控钙通道Ca(v)3.1的CACNA1G中的c.5144G > a（p.a g1715his）突变引起的。在这里，我们描述了一个患有SCA42的日本大家庭。死后病理检查显示严重的小脑变性，伴有明显的浦肯野细胞丢失，无泛素积累。为了确定这种突变是否会引起心衰症状和神经退行性变，我们产生了Cacna1g中含有c.5168G > A （p.a g1723his）突变的敲入小鼠，该突变与SCA42家族中发现的突变相对应。杂合子和纯合子突变体在11-20周龄时均出现共济失调表型，在50周龄时出现浦肯野细胞丢失。纯合敲入小鼠浦肯野细胞退行性改变和分子层萎缩变薄明显。利用幼鼠急性小脑片对浦肯野细胞进行电生理分析，发现点突变改变了Ca(v)3.1通道激活的电压依赖性，降低了超极化后的反弹动作电位，但对突触传递到浦肯野细胞的基本特性没有显著影响。最后，我们发现敲入小鼠下榄核神经元膜电位共振降低，这表明p.a g1723his Ca(v)3.1突变影响了攀爬纤维向浦肯野细胞的信号传导。总之，我们的研究表明，在小鼠模型中，CACNA1G的点突变不仅导致共济失调表型和浦肯野细胞变性，而且在SCA42早期的电生理异常先于浦肯野细胞丧失。
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 Ca(v)3.1. 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 Ca(v)3.1 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 Ca(v)3.1 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.