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Molecular Genetic basis of neural selection by cell death during development and pathological condition

发育和病理条件下细胞死亡神经选择的分子遗传学基础

基本信息

批准号：
15100007
负责人：
MIURA Masayuki
金额：
$ 76.21万
依托单位：
Graduate School of Pharmaceutical Sciences, The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (S)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2006
项目状态：
已结题

项目摘要

Programmed cell death and neurodegeneration occur in the brain. To elucidate the mechanisms of neural cell death including neurodegeneration, we developed a novel screen for genes involved in the neuronal cell death associated with neurodegeneration, involving the overexpression of individual genes throughout much of the Drosophila genome (GS screening). As a result of the screen of approximately 5000 fly strains, we identified and characterized the endd2 gene, which encodes the Drosophila ortholog of Sec61α (DSec61α) located in endoplasmic reticulum, as a new component of the neural cell death and degeneration pathways. We then performed a dominant-modifier screen of reaper for identification of neural-cell death related genes using a set of deficiency strains that cover more than 70% of the Drosophila genome. In this screening, we identified DmIKKε as a candidate component in the pathway of Reaper-induced cell death. DmIKKε was also identified as a candidate gene of neural cell death promoting gene in GS screening. Biochemical studies indicated that DmIKKε that promotes degradation of Drosophila IAP (DIAP 1) through direct phosphorylation. Inactivation of DmIKKε causes DIAP 1 accumulation without affecting developmental cell death. DmIKKε is a DIAP 1-degrading kinase that regulates endogenous levels of DIAP 1, which in turn regulates neural cell fate through non-apoptotic functions of caspases in vivo.

程序性细胞死亡和神经变性发生在大脑中。为了阐明包括神经变性在内的神经细胞死亡的机制，我们开发了一种新的基因筛选方法，用于筛选与神经变性相关的神经细胞死亡所涉及的基因，涉及果蝇基因组大部分中单个基因的过度表达（GS筛选）。通过对约 5000 个果蝇品系的筛选，我们鉴定并表征了 endd2 基因，该基因编码位于内质网的果蝇 Sec61α (DSec61α) 直系同源物，作为神经细胞死亡和变性途径的新组成部分。然后，我们使用一组覆盖果蝇基因组 70% 以上的缺陷菌株，对收割者进行了显性修饰筛选，以鉴定神经细胞死亡相关基因。在此筛选中，我们将 DmIKKε 鉴定为 Reaper 诱导的细胞死亡途径中的候选成分。 DmIKKε在GS筛选中也被鉴定为神经细胞死亡促进基因的候选基因。生化研究表明，DmIKKε 通过直接磷酸化促进果蝇 IAP (DIAP 1) 的降解。 DmIKKε 失活会导致 DIAP 1 积累，但不会影响发育细胞死亡。 DmIKKε 是一种 DIAP 1 降解激酶，可调节 DIAP 1 的内源水平，进而通过体内半胱天冬酶的非凋亡功能调节神经细胞的命运。