Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra
Dysregulation of gene expression in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse substantia nigra
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DOI：
10.1523/jneurosci.4204-03.2004
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发表时间：
2004-08-25
影响因子：
5.3
通讯作者：
Federoff, HJ
中科院分区：
文献类型：
--
作者：
Miller, RM;Callahan, LM;Federoff, HJ
帕金森氏病的发病经历了几个阶段，最终以黑质多巴胺能神经元的丧失而告终。虽然氧化性SN损伤的1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）模型经常被用于研究小鼠和非人灵长类动物多巴胺能神经元的退化，但从线粒体复合物1的抑制到神经元细胞死亡的分子事件的时间序列的理解有限。本研究使用微阵列分析和综合数据挖掘来揭示MPTP给药后多巴胺能神经元变化进程的相关途径。这种方法能够识别mptp处理动物SN内基因表达的微小但持续显著的变化。这样的分析揭示了与神经元功能相关的三个主要领域的基因失调：细胞骨架稳定性和维持，突触完整性，细胞周期和凋亡。这些改变的发现和验证为损伤、功能障碍和细胞死亡的进化级联提供了分子证据。
Parkinson's disease pathogenesis proceeds through several phases, culminating in the loss of dopaminergic neurons of the substantia nigra (SN). Although the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ( MPTP) model of oxidative SN injury is frequently used to study degeneration of dopaminergic neurons in mice and non-human primates, an understanding of the temporal sequence of molecular events from inhibition of mitochondrial complex 1 to neuronal cell death is limited. Here, microarray analysis and integrative data mining were used to uncover pathways implicated in the progression of changes in dopaminergic neurons after MPTP administration. This approach enabled the identification of small, yet consistently significant, changes in gene expression within the SN of MPTP-treated animals. Such an analysis disclosed dysregulation of genes in three main areas related to neuronal function: cytoskeletal stability and maintenance, synaptic integrity, and cell cycle and apoptosis. The discovery and validation of these alterations provide molecular evidence for an evolving cascade of injury, dysfunction, and cell death.