A role for voltage-dependent anion channel Vdac1 in polyglutamine-mediated neuronal cell death.
A role for voltage-dependent anion channel Vdac1 in polyglutamine-mediated neuronal cell death.
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电压依赖性阴离子通道VDAC1在多谷氨酸介导的神经元细胞死亡中的作用。
DOI：
10.1371/journal.pone.0001170
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发表时间：
2007-11-14
期刊：
影响因子：
3.7
通讯作者：
Pillai B
中科院分区：
文献类型：
--
作者：
Ghosh T;Pandey N;Maitra A;Brahmachari SK;Pillai B
基因编码区和非编码区三核苷酸重复序列的扩增与16种神经退行性疾病相关。然而，导致神经变性的分子效应仍然难以捉摸。我们已经探讨了转录失调的作用TATA盒结合蛋白（TBP）含有扩大聚谷氨酰胺拉伸在小鼠神经细胞培养为基础的模型。我们发现，小鼠神经元细胞表达的变体的人TBP窝藏异常扩大polyQ道不仅形成核内聚集体，但也显示转录失调的电压依赖性阴离子通道，Vdac1，增加细胞色素c释放的线粒体和上调基因参与本地化神经元翻译。另一方面，未折叠的蛋白质反应似乎不受影响。与增加的转录效应一致，我们观察到TBP在体内在含TATA和无TATA的差异表达基因启动子中的启动子占用率升高。我们的研究表明，在三核苷酸重复介导的神经元功能障碍中，转录功能障碍和细胞死亡之间的联系通过电压依赖性阴离子通道Vdac1，这是最近被认为是细胞死亡的关键决定因素。
Expansion of trinucleotide repeats in coding and non-coding regions of genes is associated with sixteen neurodegenerative disorders. However, the molecular effects that lead to neurodegeneration have remained elusive. We have explored the role of transcriptional dysregulation by TATA-box binding protein (TBP) containing an expanded polyglutamine stretch in a mouse neuronal cell culture based model. We find that mouse neuronal cells expressing a variant of human TBP harboring an abnormally expanded polyQ tract not only form intranuclear aggregates, but also show transcription dysregulation of the voltage dependent anion channel, Vdac1, increased cytochrome c release from the mitochondria and upregulation of genes involved in localized neuronal translation. On the other hand, unfolded protein response seemed to be unaffected. Consistent with an increased transcriptional effect, we observe an elevated promoter occupancy by TBP in vivo in TATA containing and TATA-less promoters of differentially expressed genes. Our study suggests a link between transcriptional dysfunction and cell death in trinucleotide repeat mediated neuronal dysfunction through voltage dependent anion channel, Vdac1, which has been recently recognized as a critical determinant of cell death.
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