Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL
Polyglutamine-expanded ataxin-3 activates mitochondrial apoptotic pathway by upregulating Bax and downregulating Bcl-xL
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DOI：
10.1016/j.nbd.2005.07.011
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发表时间：
2006-02-01
影响因子：
6.1
通讯作者：
Wang, HL
中科院分区：
文献类型：
--
作者：
Chou, AH;Yeh, TH;Wang, HL
脊髓小脑性共济失调3型（SCA 3）是一种由多聚谷氨酰胺扩展型共济失调蛋白3（polyglutamine-expanded ataxin-3）引起的常染色体显性遗传神经退行性疾病。在本研究中，我们使用重组腺病毒在小脑、纹状体和黑质的神经元培养物中表达致病突变型共济失调蛋白3-Q79。随后，SCA 3细胞模型用于研究ataxin-3-Q79引起神经元死亡的分子机制。TUNEL染色结果显示，ataxin-3-Q79可诱导小脑、纹状体和黑质神经元凋亡。Ataxin-3-Q79激活caspase-3和caspase-9，而不诱导活性caspase-8的形成。Ataxin-3-Q79促进线粒体细胞色素c和Smac的释放，在此之前上调Bax蛋白和下调Bcl-x（L）蛋白的表达。Real-time TaqMan RT-PCR结果显示，ataxin-3-Q79可上调纹状体、小脑和黑质神经元Bax mRNA表达，下调Bcl-x（L）mRNA表达。我们的研究结果表明，聚谷氨酰胺扩展的ataxin-3-Q79激活线粒体凋亡途径，并通过上调Bax表达和下调Bcl-x（L）表达诱导神经元死亡。(c)2005年爱思唯尔公司All rights reserved.
Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-3. In the present study, we expressed disease-causing mutant ataxin-3-Q79 in neuronal cultures of cerebellum, striatum and substantia nigra by using recombinant adenoviruses. Subsequently, SCA3 cellular model was used to investigate the molecular mechanism by which ataxin-3-Q79 causes neuronal death. TUNEL staining studies showed that ataxin-3-Q79 induced apoptotic death of cerebellar, striatal or substantia nigra neurons. Ataxin-3-Q79 activated caspase-3 and caspase-9 without inducing the formation of active caspase-8. Ataxin-3-Q79 promoted mitochondrial release of cytochrome c and Smac, which was preceded by the upregulation of Bax protein and downregulation of Bcl-x(L) protein expression. Real-time TaqMan RT-PCR assays demonstrated that ataxin-3-Q79 upregulated Bax mRNA level and downregulated Bcl-x(L) mRNA expression in striatal, cerebellar and substantia nigra neurons. Our results suggest that polyglutamine-expanded ataxin-3-Q79 activates mitochondrial apoptotic pathway and induces neuronal death by upregulating Bax expression and downregulating Bcl-x(L) expression. (c) 2005 Elsevier Inc. All rights reserved.