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受细胞死亡的因素。黑质纹状体DA （NSDA）、中边缘DA （MLDA）和下丘脑结节底叶DA （TIDA）在暴露于抑制线粒体复合体I的毒素后表现出不同程度的毒性，这种模式与PD患者这些神经元群的区域变性相似。NSDA神经元非常脆弱，而其他DA神经元对PD的神经毒素暴露和变性表现出部分（MLDA）或完全（TIDA）抗性。在这三种不同的多巴胺能神经元群体中，选择性神经毒素易感性的机制尚不清楚。我们假设，细胞保护基因的区域特异性神经元表达，而不是神经元外的微环境因素，决定了TIDA和MLDA下丘脑DA神经元对MPTP毒性作用和PD变性的相对抗性。为了解决这一假设，提出了以下具体目标：

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.