Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by symptoms that include involuntary movement of the body, loss of cognitive function, psychiatric disorders, and inevitable death (Ehrnhoefer et al., 2009, Labbadia and Morimoto, 2013). HD is an autosomal dominant disease caused by poly-glutamine expansion in a protein named huntingtin (Htt), leading to aggregate formation, as in a typical case of protein misfolding (Li and Li, 2004). However, the molecular mechanisms linking Htt mutation and neuronal cell death have not yet been fully elucidated (Davies et al., 1997, Tobin and Signer, 2000, Labbadia and Morimoto, 2013). The development of HD is determined by the progressive neuronal cell death occurring in the neocortex and striatum of affected patients (DiFiglia, 1990). There are some data showing that the neuronal cell loss that takes place in HD is due to glutamatergic excitotoxicity, which is mediated by excessive influx of intracellular Ca²⁺ (DiFiglia, 1990, Calabresi et al., 1999). Several studies indicate that mHtt promotes Ca²⁺ signaling alterations, which might be closely associated with the death of striatal neurons (Oliveira et al., 2006, Rosenstock et al., 2010, Wu et al., 2016, Raymond, 2017). It has been described that high levels of intracellular Ca²⁺ produce abnormalities in the central nervous system that might be associated with voltage-gated Ca²⁺ channels (Sattler and Tymianski, 2000, Cano-Abad et al., 2001, Luo et al., 2005, Swayne et al., 2005, Kim et al., 2008, Min et al., 2013). Alterations of voltage-gated channels may play an important part in disorders such as Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, and ischemia (Kim and Rhim, 2004, Pierrot et al., 2004, Luo et al., 2005, Swayne et al., 2005, Wu et al., 2011). Furthermore, dysfunction of L-type Ca²⁺ channels has been implicated in some of the most prevalent neurodegenerative diseases, including AD and PD (Hurley et al., 2013, Min et al., 2013). Notably, previous studies have demonstrated that high levels of Ca_v1.2 channel expression in the brain are involved in AD (Kim and Rhim, 2011), and additional data showed that isradipine, an L-type Ca²⁺ channel blocker, offers neuroprotection in a mouse model of PD (Ilijic et al., 2011). Therefore, we attempted to investigate whether Ca_v1 channels played a role on HD using a bacterial artificial chromosome (BAC)-mediated transgenic mouse model, BACHD (Gray et al., 2008). BACHD mice express full-length human Htt, exhibit progressive motor deficits, and late-onset selective neurodegeneration in the cortex and striatum. Accordingly, this mouse model is well suited for therapeutic trials (Ehrnhoefer et al., 2009).

中文翻译：

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钙通道在亨廷顿氏病和CaV1通道受阻的神经保护的小鼠模型中的变化。

亨廷顿舞蹈病（HD）是一种进行性神经退行性疾病，其症状包括身体不自主运动，认知功能丧失，精神病和不可避免的死亡（Ehrnhoefer等，2009; Labbadia和Morimoto，2013）。HD是一种常染色体显性遗传疾病，是由称为huntingtin（Htt）的蛋白质中的聚谷氨酰胺膨胀引起的，导致聚集体形成，就像典型的蛋白质错误折叠情况一样（Li和Li，2004）。但是，尚未充分阐明将Htt突变与神经元细胞死亡联系起来的分子机制（Davies等，1997； Tobin和Signer，2000； Labbadia和Morimoto，2013）。HD的发展取决于患病患者的新皮层和纹状体中发生的进行性神经元细胞死亡（DiFiglia，1990）。²⁺（DiFiglia，1990； Calabresi等，1999）。数项研究表明mHtt促进Ca ²⁺信号改变，这可能与纹状体神经元的死亡密切相关（Oliveira等人，2006; Rosenstock等人，2010; Wu等人，2016; Raymond，2017）。据描述，高水平的细胞内Ca ²⁺会在中枢神经系统中产生异常现象，这可能与电压门控的Ca ^2+有关。通道（Sattler和Tymianski，2000，Cano-Abad等，2001，Luo等，2005，Swayne等，2005，Kim等，2008，Min等，2013）。电压门控通道的改变可能在阿尔茨海默氏病（AD），帕金森氏病（PD），癫痫和局部缺血等疾病中起重要作用（Kim和Rhim，2004； Pierrot等，2004； Luo等， 2005，Swayne等，2005，Wu等，2011）。此外，L型Ca ²⁺通道功能异常也涉及某些最普遍的神经退行性疾病，包括AD和PD（Hurley等，2013； Min等，2013）。值得注意的是，先前的研究表明，大脑中高水平的Ca _v 1.2通道表达与AD有关（Kim和Rhim，2011年），另外的数据表明，L型Ca异烟碱²⁺通道阻滞剂可在PD小鼠模型中提供神经保护作用（Ilijic等，2011）。因此，我们尝试使用细菌人工染色体（BAC）介导的转基因小鼠模型BACHD研究Ca _v 1通道是否在HD上发挥作用（Gray等，2008）。BACHD小鼠表达全长人类Htt，表现出进行性运动缺陷，并在皮质和纹状体中出现迟发的选择性神经变性。因此，该小鼠模型非常适合治疗试验（Ehrnhoefer等，2009）。