SELECTIVE VULNERABILITY OF DOPAMINE NEURONS IN PARKINSON'S DISEASE

帕金森病中多巴胺神经元的选择性脆弱性

• 批准号: 6347674
• 负责人: John B Penney
• 金额: $ 12.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347674
• 关键词: Parkinson's disease; age difference; alpha synuclein; dopamine; dopamine transporter; dystonia; human genetic material tag; human tissue; mesencephalon; nerve /myelin protein; neurons; neuropathology

Not all dopamine neurons are equally vulnerable to degeneration in idiopathic Parkinson's disease (PD). "Nigrosomes" of substantia nigra pars compacts are most vulnerable with nigral matrix, retrorubral area and ventral tegmental area next in vulnerability while hypothalamic and periaqueductal gray neurons are resistant to the degenerative process. This project will test the hypothesis that the dopamine neurons most vulnerable to parkinsonian degeneration differ from relatively resistant neurons by having higher concentrations of molecules that make them vulnerable to degeneration (alpha-synuclein, recently found to be mutated in some PD families and to be present in Lewy bodies; parkin, recently found to be mutated in autosomal recessive-juvenile parkinsonism; torsinA, the dopamine neuron chaperonin that is mutated in early onset torsion dystonia; or dopamine transporters). The newly developed double-label in situ hybridization histochemistry and antisense RNA techniques will be used to compare the gene expression rates of these compounds in the different subgroups of dopamine neurons in control brains and in the brains of persons dying with PD. In collaboration with projects 1, 2 and 4, ligand binding studies will be done to study dopamine and GABA function in the basal ganglia of mice transgenic for the alpha-synuclein and torsinA mutations. These experiments are important for testing the overall hypothesis that specific molecules are important to PD pathogenesis since they will link these molecules directly to the effected neurons while generalized evidence for changes in their expression in PD might be a result from rather a cause of the disease process.

并不是所有的多巴胺神经元都同样容易退化， 特发性帕金森病（PD）。黑质部的“黑小体” 黑质基质、红核后区和 腹侧被盖区其次，下丘脑和 导水管周围灰质神经元对变性过程有抵抗力。 该项目将测试多巴胺神经元最多的假设 易受帕金森病变性的影响不同于相对抵抗 神经元的分子浓度更高， 易变性（α-突触核蛋白，最近发现突变 在一些PD家庭和存在于路易体;帕金，最近 发现在常染色体隐性-青少年帕金森综合征中突变;扭转蛋白A， 在早发性扭转中突变的多巴胺神经元伴侣蛋白 肌张力障碍;或多巴胺转运蛋白）。新开发的双标记在 原位杂交组织化学和反义RNA技术， 用于比较这些化合物在小鼠中的基因表达率。 在对照组和对照组的大脑中， 死于帕金森病的人的大脑与项目1、2和 4、通过配体结合实验研究多巴胺和GABA的功能 在α-突触核蛋白转基因小鼠的基底神经节中， torsinA突变。这些实验对于测试整体 假设特定分子对PD发病机制很重要， 它们将这些分子直接连接到受影响的神经元， PD中它们表达变化的普遍证据可能是一种 而是由疾病过程的原因引起的。