Identification of neurodegenerative factors using translatome-regulatory network analysis
Identification of neurodegenerative factors using translatome-regulatory network analysis
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DOI：
10.1038/nn.4070
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发表时间：
2015-09-01
影响因子：
25
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
--
作者：
Brichta, Lars;Shin, William;Greengard, Paul
对于中枢神经系统退行性疾病，治疗进展的主要障碍一直是确定神经元丢失的关键分子机制的挑战。我们开发了一种组合方法，包括翻译图谱和大脑调节网络分析，以寻找神经元生存或死亡的关键决定因素。随着中脑多巴胺能神经元细胞类型特异性分析的转基因小鼠的产生，我们建立并比较了反映这些细胞在基线或退化应激下的分子特征的翻译组文库。通过询问特定背景的大脑调节网络对这些文库进行分析，发现了驱动多巴胺能应激反应的一系列内在上游调节因子。这些调节因子活性的改变与其表达水平的变化无关。这一策略可以推广到识别与其他类型神经元退化有关的分子决定因素。
For degenerative disorders of the CNS, the main obstacle to therapeutic advancement has been the challenge of identifying the key molecular mechanisms underlying neuronal loss. We developed a combinatorial approach including translational profiling and brain regulatory network analysis to search for key determinants of neuronal survival or death. Following the generation of transgenic mice for cell type-specific profiling of midbrain dopaminergic neurons, we established and compared translatome libraries reflecting the molecular signature of these cells at baseline or under degenerative stress. Analysis of these libraries by interrogating a context-specific brain regulatory network led to the identification of a repertoire of intrinsic upstream regulators that drive the dopaminergic stress response. The altered activity of these regulators was not associated with changes in their expression levels. This strategy can be generalized for the identification of molecular determinants involved in the degeneration of other classes of neurons.