Omi/HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease
Omi/HtrA2 is relevant to the selective vulnerability of striatal neurons in Huntington's disease
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DOI：
10.1111/j.1460-9568.2008.06323.x
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发表时间：
2008-07-01
影响因子：
3.4
通讯作者：
Okazawa, Hitoshi
中科院分区：
文献类型：
--
作者：
Inagaki, Reina;Tagawa, Kazuhiko;Okazawa, Hitoshi
神经元的选择性易感性是神经退行性疾病的一个重要特征，但其潜在的分子机制在很大程度上仍然未知。我们在此报告Omi/HtrA2，一种调节细胞存活和凋亡的线粒体蛋白，在最易受亨廷顿病（HD）病理影响的纹状体神经元中选择性减少。微阵列分析显示，在纹状体神经元中表达突变型亨廷顿蛋白（htt）时，Omi/HtrA2水平降低，而在皮质和小脑神经元中则没有。ataxin-1突变体（Atx-1）不影响任何类型神经元的Omi/HtrA2。表达突变体htt的原代神经元的Western blot分析也证实了Omi/HtrA2蛋白的选择性减少。用htt转基因突变小鼠系和人类HD大脑进行免疫组化，证实纹状体神经元中Omi/HtrA2的表达减少。腺病毒载体过表达Omi/HtrA2诱导原代神经元细胞死亡。这些结果共同表明，Omi/HtrA2的稳态功能而非促凋亡功能与HD病理中纹状体神经元的选择性易感性有关。
Selective vulnerability of neurons is a critical feature of neurodegenerative diseases, but the underlying molecular mechanisms remain largely unknown. We here report that Omi/HtrA2, a mitochondrial protein regulating survival and apoptosis of cells, decreases selectively in striatal neurons that are most vulnerable to the Huntington's disease (HD) pathology. In microarray analysis, Omi/HtrA2 was decreased under the expression of mutant huntingtin (htt) in striatal neurons but not in cortical or cerebellar neurons. Mutant ataxin-1 (Atx-1) did not affect Omi/HtrA2 in any type of neuron. Western blot analysis of primary neurons expressing mutant htt also confirmed the selective reduction of the Omi/HtrA2 protein. Immunohistochemistry with a mutant htt-transgenic mouse line and human HD brains confirmed reduction of Omi/HtrA2 in striatal neurons. Overexpression of Omi/HtrA2 by adenovirus vector reverted mutant htt-induced cell death in primary neurons. These results collectively suggest that the homeostatic but not proapoptotic function of Omi/HtrA2 is linked to selective vulnerability of striatal neurons in HD pathology.