Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity
Gain-of-function screen identifies a role of the Sec61α translocon in Drosophila postmitotic neurotoxicity
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DOI：
10.1016/j.bbagen.2005.06.020
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发表时间：
2005-11-30
影响因子：
3
通讯作者：
Miura, M
中科院分区：
文献类型：
--
作者：
Kanuka, H;Hiratou, T;Miura, M
为了阐明神经毒性诱导的内在机制，包括神经细胞死亡和神经变性的潜在机制，我们开发了一种针对导致神经细胞损失的基因产物的功能获得性筛选。为了鉴定神经元中具有细胞死亡相关功能的新基因，我们筛选了 4,964 个果蝇 GS 系，其中大部分果蝇基因组中的一两个基因可以过表达。大约 0.68% 的 GS 系产生涉及有丝分裂后神经元丢失的表型。其中，我们鉴定并表征了 endd2 基因，该基因编码果蝇 Sec61 α (DSec61 α) 的直系同源物，Sec61 α 是一种具有蛋白质易位活性的内质网蛋白。 DSec61 α 的异位表达导致神经细胞死亡，并伴有泛素化蛋白的积累，这是由 DSec61 α 的易位子活性介导的。这支持了我们之前的观察，即 DSec61 α 易位子会导致多聚谷氨酰胺介导的神经元毒性扩大，这也与泛素化蛋白的积累有关。这些数据表明易位子可能是神经细胞死亡和退化途径的新组成部分。我们的方法可用于识别整个基因组内潜在的神经毒性因子，这将增加我们对各种类型细胞死亡的分子机制的理解，包括与人类神经退行性疾病相关的细胞死亡。 (c) 2005 Elsevier B.V. 保留所有权利。
To elucidate the intrinsic mechanisims of neurotoxicity induction, including those underlying neural cell death and neurodegeneration, we developed a gain-of-function screen for gene products causing neural cell loss. To identify novel genes with a cell-death-related function in neurons, we screened 4,964 Drosophila GS lines, in which one or two genes from much of the Drosophila genome can be overexpressed. Approximately 0.68% of the GS lines produced phenotypes involving a loss of postmitotic neurons. Of these, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61 alpha (DSec61 alpha), an endoplastnic reticulum protein with protein translocation activity. Ectopic expression of DSec61 alpha caused neural cell death accompanied by the accumulation of ubiquitinated proteins, which was mediated by DSec61 alpha's translocon activity. This supported our previous observation that the DSec61 alpha translocon contributes to expanded polyglutamine-mediated neuronal toxicity, which is also associated with ubiquitinated protein accumulation. These data suggest that the translocon may be a novel component of neural cell death and degeneration pathways. Our approach can be used to identify potential neurotoxic factors within the whole genome, which will increase our understanding of the molecular mechanisms of various types of cell death, including those associated with human neurodegenerative diseases. (c) 2005 Elsevier B.V. All rights reserved.