Neuroprotective factors in hypothalamic dopamine neurons

描述(申请人提供)：多巴胺(DA)神经元表现出不同的神经毒素敏感性，这可能有助于深入了解保护多巴胺能神经元免受细胞死亡的因素。黑质纹状体DA(NSDA)、中脑边缘DA(MLDA)和下丘脑漏斗状结节DA(TIDA)在暴露于抑制线粒体复合体I的毒素后显示出不同程度的毒性，这种模式与PD这些神经元群体的区域性退化相似。NSDA神经元非常脆弱，而其他DA神经元似乎部分(MLDA)或完全(TIDA)抵抗神经毒素暴露和PD的变性。在这三种不同的多巴胺能神经元中，选择性神经毒素脆弱性的机制还知之甚少。我们假设，细胞保护基因的区域特异性神经元表达，而不是神经元外微环境因素，决定了TIDA和MLDA下丘脑DA神经元对MPTP毒性效应和PD变性的相对抵抗力。为了解决这一假设，提出了以下具体目标： 1.研究慢性暴露于线粒体复合体I抑制剂后，NSDA、MLDA和下丘脑Tida神经元对神经毒素敏感性的区域性差异。2.体外研究NSDA、MLDA和下丘脑Tida神经元对应的原代DA神经元对神经毒素的不同敏感性。3.比较和对比基础状态和慢性线粒体复合体I抑制后小鼠NSDA、MLDA和下丘脑Tida神经元的mRNA表达表型。4.比较帕金森病患者和年龄匹配对照组NSDA、MLDA和下丘脑Tida神经元的mRNA表达表型。

DESCRIPTION (provided by applicant): Dopamine (DA) neurons exhibit differential neurotoxin susceptibility that may provide insight into factors protecting dopaminergic neurons from cell death. Nigrostriatal DA (NSDA), mesolimbic DA (MLDA), and hypothalamic tuberoinfundibular DA (TIDA) display disparate degrees of toxicity following exposure to toxins inhibiting mitochondrial complex I, a pattern that parallels the regional degeneration of these neuronal populations in PD. NSDA neurons are exquisitely vulnerable, while other DA neurons appear partially (MLDA) or completely (TIDA) resistant to neurotoxin exposure and degeneration in PD. The mechanisms of selective neurotoxin vulnerability in these three distinct populations of dopaminergic neurons are poorly understood. We hypothesize that region-specific neuronal expression of cytoprotective genes, rather than extraneuronal microenvironmental factors, determine the relative resistance of TIDA and MLDA hypothalamic DA neurons to the toxic effects of MPTP and to degeneration in PD. To address this hypothesis, the following specific aims are proposed: 1. To demonstrate regional differences in neurotoxin susceptibility in NSDA, MLDA, and hypothalamic TIDA neurons following chronic exposure to mitochondrial complex I inhibitors in vivo. 2. To determine if primary DA neurons corresponding to NSDA, MLDA and hypothalamic TIDA neurons have differential sensitivity to neurotoxin exposure in vitro. 3. To compare and contrast mRNA expression phenotypes in NSDA, MLDA and hypothalamic TIDA neurons in mice under basal conditions and following chronic mitochondrial complex I inhibition. 4. To compare and contrast mRNA expression phenotypes in NSDA, MLDA and hypothalamic TIDA neurons of patients with PD and from age-matched controls.