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Downregulation of sodium channel β4 subunit in Huntington Disease transgenic mice

亨廷顿病转基因小鼠钠通道β4亚基的下调

基本信息

批准号：
20500329
负责人：
OYAMA Fumitaka
金额：
$ 2.91万
依托单位：
The Institute of Physical and Chemical Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2008
资助国家：
日本
起止时间：
2008 至 2010
项目状态：
已结题

项目摘要

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.

钠通道β4（β4）是最近发现的电压门控钠通道的辅助亚基。我们确定β4是在亨廷顿病（HD）模型小鼠和患者的纹状体中显著下调的EST。为了确定β4表达降低的分子机制，我们在脑中产生在小鼠β4启动子控制下表达Venus的转基因小鼠品系。我们建立了六个小鼠品系，主要在纹状体，皮质或纹状体和皮质中表现出Venus表达。将在纹状体中表现出优势Venus表达的小鼠系与HD模型小鼠杂交以产生双转基因小鼠。β4启动子-Venus转基因缺失外显子-内含子结构和3 '-UTR的Venus基因转录产物及内源性β4在双转基因小鼠纹状体中表达下调。Venus表达在扩增的携带多聚谷氨酰胺的细胞的核积累（NA）中减少，而在不携带NA的细胞中保留。这些结果表明，β4在HD模型小鼠中的下调依赖于其启动子和扩增的多聚谷氨酰胺的核积累（NA）。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Mutant Huntingtin reduces HSP70 expression through the sequestration of NF‐Y transcription factor

DOI：
10.1038/emboj.2008.23
发表时间：
2008-03
期刊：
The EMBO Journal
影响因子：
0
作者：
T. Yamanaka;Haruko Miyazaki;F. Oyama;M. Kurosawa;Chika Washizu;H. Doi;N. Nukina
通讯作者：
T. Yamanaka;Haruko Miyazaki;F. Oyama;M. Kurosawa;Chika Washizu;H. Doi;N. Nukina

Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability