Downregulation of sodium channel β4 subunit in Huntington Disease transgenic mice

钠通道β4(β4)是新近发现的电压门控钠通道的辅助亚基。我们发现β-4是一种在亨廷顿病(HD)模型小鼠和患者的纹状体中显著下调的EST。为了明确β4表达下调的分子机制，我们建立了在小鼠脑内β4启动子控制下表达Venus的转基因小鼠系。我们建立了六个主要在纹状体、皮质或同时在纹状体和皮质表达Venus的小鼠品系。将纹状体中以Venus为主的小鼠品系与HD模型小鼠杂交，产生双转基因小鼠。双转基因小鼠纹状体中β4启动子转录的金星和缺失外显子-内含子结构的金星和3‘-非翻译区以及内源性β4的表达均下调。在扩增的聚谷氨酰胺承载细胞的核堆积(NA)中，Venus的表达减少，而在非NA承载细胞中它的表达被保留。这些结果表明，HD模型小鼠β-4的下调依赖于其启动子和扩张的聚谷氨酰胺的核积聚。

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.