Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model
Hypothesis-based RNAi screening identifies neuroprotective genes in a Parkinson's disease model
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DOI：
10.1073/pnas.0711018105
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发表时间：
2008-01-15
影响因子：
11.1
通讯作者：
Caldwell, Guy A.
中科院分区：
文献类型：
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作者：
Hamamichi, Shusei;Rivas, Renee N.;Caldwell, Guy A.
编码基因座的人α-突触核蛋白（α-syn）（一种具有细胞内错误折叠倾向的多肽）的基因组倍增导致帕金森病（PD）。在这里，我们报告了系统筛选近900个候选遗传靶点的结果，这些靶点通过RNAi敲除与现有PD基因和途径的生物信息学关联进行优先排序。消耗20个基因产物可重复地增强了线虫Caelophabditis elegans在衰老过程中的α-syn错误折叠。随后对7个阳性靶点的功能分析揭示了5种以前未报道的基因产物，这些基因产物显著地防止了转基因蠕虫多巴胺神经元中年龄和剂量依赖性α-syn诱导的变性。这些包括两种运输蛋白，一种调节G蛋白信号的保守细胞支架型蛋白，一种功能未知的蛋白，以及一种据报道在敲除小鼠中引起神经变性的基因。这些数据代表了假定的遗传易感基因座和PD的潜在治疗靶点，PD是一种影响约2%的65岁以上人群的运动障碍。
Genomic multiplication of the locus-encoding human a-synuclein (alpha-syn), a polypeptide with a propensity toward intracellular misfolding, results in Parkinson's disease (PD). Here we report the results from systematic screening of nearly 900 candidate genetic targets, prioritized by bioinformatic associations to existing PD genes and pathways, via RNAi knockdown. Depletion of 20 gene products reproducibly enhanced misfolding of alpha-syn over the course of aging in the nematode Caenorhabditis elegans. Subsequent functional analysis of seven positive targets revealed five previously unreported gene products that significantly protect against age- and dose-dependent alpha-syn-induced degeneration in the dopamine neurons of transgenic worms. These include two trafficking proteins, a conserved cellular scaffold-type protein that modulates G protein signaling, a protein of unknown function, and one gene reported to cause neurodegeneration in knockout mice. These data represent putative genetic susceptibility loci and potential therapeutic targets for PD, a movement disorder affecting approximate to 2% of the population over 65 years of age.