Abstract：
Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation. However, mutant ataxin-2 protein also displays the features of gain-of-function mutation since it forms the aggregates in SCA2 cells and also enhances the IP3-induced calcium release in affected neurons. The cerebellar Purkinje cells (PCs) are primarily affected in SCA2. Their tonic pacemaker activity is crucial for the proper cerebellar functioning. Disturbances in PC pacemaking are observed in many ataxic disorders. The abnormal intrinsic pacemaking was reported in mouse models of episodic ataxia type 2 (EA2), SCA1, SCA2, SCA3, SCA6, Huntington\'s disease (HD), and in some other murine models of the disorders associated with the cerebellar degeneration. In our studies using SCA2-58Q transgenic mice via cerebellar slice recording and in vivo recording from urethane-anesthetized mice and awake head-fixed mice, we have demonstrated the impaired firing frequency and irregularity of PCs in these mice. PC pacemaker activity is regulated by SK channels. The pharmacological activation of SK channels has demonstrated some promising results in the electrophysiological experiments on EA2, SCA1, SCA2, SCA3, SCA6, HD mice, and also on mutant CACNA1A mice. In our studies, we have reported that the SK activators CyPPA and NS309 converted bursting activity into tonic, while oral treatment with CyPPA and NS13001 significantly improved motor performance and PC morphology in SCA2 mice. The i.p. injections of chlorzoxazone (CHZ) during in vivo recording sessions converted bursting cells into tonic in anesthetized SCA2 mice. And, finally, long-term injections of CHZ recovered the precision of PC pacemaking activity in awake SCA2 mice and alleviated their motor decline. Thus, the SK activation can be used as a potential way to treat SCA2 and other diseases accompanied by cerebellar degeneration.
摘要：
脊髓小脑共济失调2型（SCA2）是一种无法治愈的遗传性疾病，伴有共济失调症状后的小脑变性。SCA2的致病基因是ATXN2。ataxin-2蛋白参与RNA代谢；polyQ扩增可能会中断ataxin-2与其分子靶标的相互作用，因此代表功能丧失突变。然而,突变型ataxin-2蛋白还表现出功能获得突变的特征,因为它在SCA2细胞中形成聚集体,并且还增强受影响神经元中IP3诱导的钙释放。小脑浦肯野细胞（PC）主要在SCA2中受到影响。他们的补品起搏器活动对于正常的小脑功能至关重要。在许多共济失调性疾病中观察到PC起搏的紊乱。在2型发作性共济失调（EA2）的小鼠模型中报告了异常的内在起搏，SCA1，SCA2，SCA3，SCA6，亨廷顿病（HD），以及其他一些与小脑变性相关的疾病的小鼠模型。在我们的研究中，使用SCA2-58Q转基因小鼠通过小脑切片记录和乌拉坦麻醉小鼠和清醒头部固定小鼠的体内记录，我们已经证明了这些小鼠中PC的放电频率和不规则性受损。PC起搏器活动由SK通道调节。SK通道的药理激活在EA2，SCA1，SCA2，SCA3，SCA6，HD小鼠的电生理实验中显示出一些有希望的结果，以及突变的CACNA1A小鼠。在我们的研究中,我们已经报道，SK活化剂CyPPA和NS309将破裂活性转化为补品，而CyPPA和NS13001口服治疗可显着改善SCA2小鼠的运动性能和PC形态。在体内记录期间腹膜内注射氯唑沙宗(CHZ)将破裂细胞转化为麻醉的SCA2小鼠中的补品。And,最后,长期注射CHZ可以恢复清醒SCA2小鼠的PC起搏活动的准确性，并减轻其运动能力下降。因此，SK激活可作为治疗SCA2等伴有小脑变性的疾病的潜在途径。
