Compromised mitochondrial complex II in models of Machado-Joseph disease.
Compromised mitochondrial complex II in models of Machado-Joseph disease.
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DOI：
10.1016/j.bbadis.2011.10.010
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发表时间：
2012-02
影响因子：
6.2
通讯作者：
Rego, A. Cristina
中科院分区：
文献类型：
--
作者：
Laco, Mario N.;Oliveira, Catarina R.;Paulson, Henry L.;Rego, A. Cristina
马查多-约瑟夫病 (MJD)，也称为脊髓小脑共济失调 3 型，是一种遗传性显性常染色体神经退行性疾病。 ATXN3 基因中 CAG 重复序列的扩展被翻译为疾病蛋白 ataxin-3 中扩展的聚谷氨酰胺结构域。 MJD 中的选择性神经变性在包括小脑在内的几个皮质下大脑区域中很明显。线粒体功能障碍已被认为是多聚谷氨酰胺疾病中神经变性的机制。在这项研究中，我们使用不同的细胞模型和转基因小鼠来评估线粒体对 MJD 中观察到的细胞毒性的重要性。用扩增的 (Q84) ataxin-3 瞬时转染 HEK 细胞系，对 3-硝基丙酸 (3-NP)（线粒体复合物 II 的不可逆抑制剂）表现出更高的敏感性。在稳定转染的 PC6-3 细胞中也检测到对 3-NP 的敏感性增加，这些细胞以四环素调节的方式诱导表达扩增的 (Q108) ataxin-3。此外，MJD 转基因小鼠的小脑颗粒细胞比野生型小脑神经元对 3-NP 抑制更敏感。使用神经生长因子 (NGF) 分化为神经元样表型的 PC6-3 (Q108) 细胞表现出线粒体复合物 II 活性显着降低。来自 MJD 转基因小鼠模型的线粒体和来自 MJD 患者的淋巴母细胞系也显示出复合物 II 活性降低的趋势。我们的结果表明，线粒体复合物 II 活性在 MJD 中适度受损，这可能表明多聚谷氨酰胺毒性的一个共同特征。
Machado-Joseph disease (MJD), also known as Spinocerebellar Ataxia type 3, is an inherited dominant autosomal neurodegenerative disorder. An expansion of CAG repeats in the ATXN3 gene is translated as an expanded polyglutamine domain in the disease protein, ataxin-3. Selective neurodegeneration in MJD is evident in several subcortical brain regions including the cerebellum. Mitochondrial dysfunction has been proposed as a mechanism of neurodegeneration in polyglutamine disorders. In this study, we used different cell models and transgenic mice to assess the importance of mitochondria on cytotoxicity observed in MJD. Transiently transfected HEK cell lines with expanded (Q84) ataxin-3 exhibited a higher susceptibility to 3-nitropropionic acid (3-NP), an irreversible inhibitor of mitochondrial complex II. Increased susceptibility to 3-NP was also detected in stably transfected PC6-3 cells that inducibly express expanded (Q108) ataxin-3 in a tetracycline-regulated manner. Moreover, cerebellar granule cells from MJD transgenic mice were more sensitive to 3-NP inhibition than wild-type cerebellar neurons. PC6-3 (Q108) cells differentiated into a neuronal-like phenotype with nerve growth factor (NGF) exhibited a significant decrease in mitochondrial complex II activity. Mitochondria from MJD transgenic mouse model and lymphoblast cell lines derived from MJD patients also showed a trend towards reduced complex II activity. Our results suggest that mitochondrial complex II activity is moderately compromised in MJD, which may designate a common feature in polyglutamine toxicity.
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影响因子：
5.3
作者：
Bichelmeier, Ulrike;Schmidt, Thorsten;Riess, Olaf
通讯作者：
Riess, Olaf
影响因子：
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作者：
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Lesort, M
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作者：
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通讯作者：
Pittman, RN
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作者：
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通讯作者：
Wang, HL
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作者：
KAWAGUCHI, Y;OKAMOTO, T;KAKIZUKA, A
通讯作者：
KAKIZUKA, A