Neuroprotective factors in hypothalamic dopamine neurons

描述（由申请人提供）：多巴胺（DA）神经元表现出不同的神经毒素敏感性，这可能有助于了解保护多巴胺能神经元免于细胞死亡的因素。黑质纹状体DA（NSDA），mesolimbic DA（MLDA），和下丘脑tuberoinfundibular DA（TIDA）显示不同程度的毒性后，暴露于抑制线粒体复合物I的毒素，一种模式，平行于PD中这些神经元群体的区域变性。NSDA神经元是非常脆弱的，而其他DA神经元出现部分（MLDA）或完全（TIDA）抵抗神经毒素暴露和变性的PD。 在这三种不同的多巴胺能神经元群体中选择性神经毒素脆弱性的机制知之甚少。 我们假设，区域特异性的神经元表达的细胞保护基因，而不是神经元微环境因素，确定TIDA和MLDA下丘脑DA神经元的MPTP的毒性作用和PD变性的相对阻力。 为了解决这一假设，提出了以下具体目标： 1.证明在体内慢性暴露于线粒体复合物I抑制剂后，NSDA、MLDA和下丘脑TIDA神经元中神经毒素易感性的区域差异。2.确定与NSDA、MLDA和下丘脑TIDA神经元对应的原代DA神经元是否对体外神经毒素暴露具有不同的敏感性。3.比较和对比基础条件下和慢性线粒体复合物I抑制后小鼠NSDA、MLDA和下丘脑TIDA神经元的mRNA表达表型。4.比较和对比PD患者和年龄匹配的对照组的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.