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: 6219191
• 负责人: John B Penney
• 金额: $ 2.89万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6219191
• 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变性 特发性帕金森病(PD)。黑质部分的“黑体” 致密物最易出现黑质基质、后腰区和 腹侧被盖区紧随其后，而下丘脑和 中脑导水管周围灰质神经元对变性过程具有抵抗力。 这个项目将检验这样一种假设，即大多数多巴胺神经元 易患帕金森变性的人与相对耐受的人不同 通过拥有更高浓度的分子来制造神经元 易变性(α-突触核蛋白，最近发现突变 在一些帕金森氏症家族中，并出现在路易体中；帕金，最近 在常染色体隐性遗传性青少年帕金森综合征中发现突变；TorsinA， 早发性扭转中突变的多巴胺神经元伴侣蛋白 肌张力障碍；或多巴胺转运体)。新开发的双标签在 原位杂交组织化学和反义RNA技术将 用来比较这些化合物在 对照大脑和大脑中不同亚群的多巴胺神经元 帕金森病死亡者的大脑。与项目1、2和 4，将进行配体结合研究，以研究多巴胺和GABA的功能 在小鼠的基底节中转α-突触核蛋白和 TorsinA基因突变。这些实验对于测试整体 特定分子在帕金森病发病机制中起重要作用的假说 他们将这些分子直接连接到受影响的神经元，而 它们在帕金森氏病中表达变化的普遍证据可能是 更确切地说，是疾病过程的一个原因造成的。