Downregulation 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基。我们发现β4在亨廷顿病（HD）模型小鼠和患者的纹状体中是一个显著下调的EST。为了明确β4表达降低的分子机制，我们在小鼠脑内β4启动子的控制下，构建了表达Venus的转基因小鼠系。我们建立了6个主要在纹状体、皮层或纹状体和皮层中表达金星的小鼠系。将纹状体中Venus表达优势的小鼠系与HD模型小鼠杂交，获得双转基因小鼠。双转基因小鼠纹状体中缺乏外显子-内含子结构和3′-UTR的β4启动子-Venus基因转录的Venus基因表达下调，内源性β4基因表达下调。扩大后的多聚谷氨酰胺增殖细胞的细胞核积累（NA）中，金星的表达减少，而在非NA增殖细胞中，金星的表达保持不变。这些结果表明，HD模型小鼠β4的下调依赖于其启动子和扩大的多聚谷氨酰胺的核积累（NA）。

Sodium channel β4 (β4) is a recently identified auxiliary subunit of the voltage gated-sodium channels. We identified β4 as an EST that was significantly downregulated in the striatum of Huntington Disease (HD) model mice and patients. To define the molecular mechanism underlying the reduction of β4 expression, we generated transgenic mouse line expressing Venus under the control of mouse β4 promoter in brain. We established six mice lines exhibiting Venus expression primarily in striatum, cortex or both striatum and cortex. The mouse line exhibiting predominant Venus expression in striatum was crossed with HD model mice to generated double transgenic mice. The expression of Venus transcribed from β4 promoter-Venus transgene lacking exon-intron structure and 3'-UTR as well as endogenous β4 was downregulated in the striatum of double transgenic mice. Venus expression was reduced in nuclear accumulation (NA) of the expanded polyglutamine bearing cells, whereas it was preserved in non-NA bearing cells. These results indicate that downregulation of β4 in HD model mice is dependent on its promoter and nuclear accumulation (NA) of the expanded polyglutamine.