A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin.
A role of mitochondrial complex II defects in genetic models of Huntington's disease expressing N-terminal fragments of mutant huntingtin.
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DOI：
10.1093/hmg/ddt242
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发表时间：
2013-10-01
影响因子：
3.5
通讯作者：
Brouillet E
中科院分区：
文献类型：
--
作者：
Damiano M;Diguet E;Malgorn C;D'Aurelio M;Galvan L;Petit F;Benhaim L;Guillermier M;Houitte D;Dufour N;Hantraye P;Canals JM;Alberch J;Delzescaux T;Déglon N;Beal MF;Brouillet E
亨廷顿氏病（HD）是一种神经退行性疾病，由编码亨廷顿蛋白（Htt）中多谷氨酰胺束的CAG重复序列异常扩增引起。这种突变导致神经元死亡的机制尚不清楚。一种假设是线粒体缺陷可能起关键作用。为了支持这一点，线粒体复合体II （C-II）的活性在HD患者的纹状体中优先降低。在这里，我们研究了C-II在表达突变体Htt (mHtt) n端片段的HD不同遗传模型中的表达。Western blot分析显示，R6/1转基因小鼠纹状体中C-II的30 kDa铁硫亚基（Ip）的表达显著降低，而含有催化性70 kDa亚基（Fp）的FAD的表达水平无显著变化。蓝色天然凝胶分析显示，N171-82Q转基因小鼠线粒体中C-II的组装较早发生改变。在大鼠HD模型中，通过纹状体内注射编码mHtt的慢病毒载体，也证实了C-II活性和Ip蛋白表达的早期局部区域降低。用编码C-II Ip或Fp亚基的慢病毒载体感染大鼠纹状体，诱导这些蛋白的显著过表达，从而导致纹状体神经元对mHtt神经毒性的显著神经保护。这些在体内获得的结果支持了mHtt诱导的C-II结构和功能改变可能在HD纹状体神经元变性中起关键作用的假设，并且线粒体靶向治疗可能有助于治疗HD。
Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of a CAG repeat encoding a polyglutamine tract in the huntingtin (Htt) protein. The mutation leads to neuronal death through mechanisms which are still unknown. One hypothesis is that mitochondrial defects may play a key role. In support of this, the activity of mitochondrial complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied C-II expression in different genetic models of HD expressing N-terminal fragments of mutant Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron–Sulfur (Ip) subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice, while the levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed. Blue native gel analysis showed that the assembly of C-II in mitochondria was altered early in N171-82Q transgenic mice. Early loco-regional reduction in C-II activity and Ip protein expression was also demonstrated in a rat model of HD using intrastriatal injection of lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results obtained in vivo support the hypothesis that structural and functional alterations of C-II induced by mHtt may play a critical role in the degeneration of striatal neurons in HD and that mitochondrial-targeted therapies may be useful in its treatment.