Pathological roles of sodium channel β4 subunit in Huntington disease transgenic mice

钠通道β4(β4)是最近发现的电压门控钠通道的辅助亚单位，亨廷顿病(HD)是一种常染色体显性遗传性神经退行性疾病，以舞蹈症、精神障碍和痴呆为特征。HD是由亨廷顿蛋白氨基末端的多聚谷氨酰胺(PolyQ)膨胀引起的，Huntingtin是一种350 kDa的细胞质蛋白。为了寻找HD发病机制中的主要影响基因，我们使用高密度寡核苷酸阵列对HD转基因小鼠进行了分析，并确定P4是一种在HD模型小鼠和患者的纹状体中显著下调的EST。β-4在HD模型小鼠的症状前期开始降低，而其他电压门控离子通道亚基则在随后降低。相比之下，脊髓神经元只产生微不足道的扩张聚谷氨酰胺聚集体，即使在症状阶段也保持正常的β4表达水平。β4在神经细胞中的过表达促进了神经突起的延伸，增加了富含F-肌动蛋白的丝状足状突起的数量，表明它调节了神经突起的生长活动。最近，我们发现β4是β位点APP裂解酶的新底物，BACE1是一种膜结合的天冬氨酸蛋白酶，可以裂解淀粉样前体蛋白(APP)。当BACE1和β4共同表达时，轴突伸展速度进一步加快，丝状突起数量减少。此外，β4在海马区原代神经元中的过度表达导致神经元内树突的增厚和树突棘密度的增加。这些结果提示，β-4基因的下调可能导致HD转基因小鼠和HD患者纹状体钠通道和轴突变性的异常。

Sodium channelβ4 (β4) is a very recently identified auxiliary subunit of the voltage gated-sodium channels Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterized by chorea, psychiatric disturbances and dementia. HD is caused by a polyglutamine (polyQ) expansion in the amino terminus of huntingtin, a 350 kDa cytoplasmic protein. To find primarily affected gene in HD pathogenesis, we profiled HD transgenic mice using a high-density oligonucleotide array and identified P4 as an EST that was significantly downregulated in the striatum of HD model mice and patients. Reduction ofβ4 started at a presymptomatic stage of the HD model mice, whereas other voltage-gated ion channels subunits were decreased later. In contrast, spinal cord neurons, which generate only negligible levels of expanded polyglutamine aggregates, maintained normal levels of β4 expression even at the symptomatic stage. Overexpression of β4 in Neuro2a cells promoted neurite extension and increased the number of F-actin rich filopodia-like protrusions, indicating that 134 modulates neurite outgrowth activities. Recently we identified β4 as a new substrate for β-site APP cleaving enzyme (BACE1), a membrane-bound aspartyl protease that cleaves amyloid precursor protein (APP). While coexpression of BACE1 together with β4 further accelerated neurite extension, the number of filopodia-like protrusions was reduced. Furthermore, overexpression of β4 in hippocampal primary neurons caused a thickening of dendrites and increased density of dendritic spines in the neurons. These results suggest that downregulation in β4 may lead to abnormalities of sodium channel and neurite degeneration in the striatum of HD transgenic mice and HD patients.