SYNUCLEIN AGGREGATION AND NEURODEGENATION IN TRANSGENICS

转基因中的突触核蛋白聚集和神经变性

• 批准号: 6382363
• 负责人: DONATO A DI MONTE
• 金额: $ 31.76万
• 依托单位: PARKINSON'S INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-04-01 至 2005-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6382363
• 关键词: 6 hydroxydopamine; Lewy body; genetically modified animals; laboratory mouse; methamphetamine; methylphenyltetrahydropyridine; nerve /myelin protein; neural degeneration; neurotoxicology; proteasome; substantia nigra

DESCRIPTION: (Verbatim from the Applicant's Abstract) The relationship between alpha-synuclein, Lewy body-like inclusions and nigrostriatal degenerated will be evaluated using transgenic mice in which the human wild-type or mutant (A53T) forms of alpha-synuclein are overexpressed under the tyrosine hydroxylase promoter. The first hypothesis to be tested is that overexpression of human alpha-synuclein itself leads to neurodegenerative changes. Changes in the number o dopaminergic neurons in the substantia nigra, alterations in striatal dopaminergic terminals, and the possible formation of Lewy body-like inclusions will be compared in overexpressing mice vs. controls of different ages. The second hypothesis is that overexpression of alpha-synuclein increases the vulnerability f the nigrostriatal system to neurotoxic injury. Mice will be exposed to MPTP, 6-hydroxydopamine, or methamphetamine, and assessed for cell damage and inclusion body formation in the nigrostriatal system The third hypothesis is that an impairment of proteasome activity play a role in alpha-synuclein aggregation and consequent neurodegeneration. The effects of proteasome inhibition the formation of Lewy body-like inclusions will be compared in mice overexpressing alpha-synuclein vs. nonoverexpressing controls in the presence and absence of neurotoxic exposure. Results of these experiments should help to elucidate the mechanism of alpha-synuclein-induced neurodegeneration in familial and sporadic cases of human Parkinsonism. Transgenic mice overexpressing alpha-synuclein are also likely to be a suitable model for studying the mechanism of formation and role of Lewy body-like inclusions in nigrostriatal degeneration. Finally, findings could provide clues s to why the aging nigrostriatal system becomes more susceptible to neurodegeneration.

描述：（逐字来自申请人的摘要） α-突触核蛋白、Lewy体样内含物和黑质纹状体退化意志 使用转基因小鼠进行评估，其中人野生型或突变体 （A53 T）形式的α-突触核蛋白在酪氨酸磷酸化下过表达。 羟化酶启动子第一个要检验的假设是， 人类α-突触核蛋白本身会导致神经退行性变化。变化 黑质多巴胺能神经元的数量， 纹状体多巴胺能末梢，以及Lewy小体样的可能形成 将在过表达的小鼠中与不同的对照中比较包涵体。 年龄第二个假设是α-突触核蛋白的过度表达增加了 黑质纹状体系统对神经毒性损伤的脆弱性。小鼠将被 暴露于MPTP、6-羟基多巴胺或甲基苯丙胺，并评估细胞 黑质纹状体系统的损伤和包涵体的形成 假设是蛋白酶体活性受损在 α-突触核蛋白聚集和随后的神经变性。的影响 蛋白酶体抑制路易体样包涵体的形成， 在过表达α-突触核蛋白的小鼠与非过表达对照小鼠中进行比较 在存在和不存在神经毒性暴露的情况下。结果进行 实验应该有助于阐明α-突触核蛋白诱导的 家族性和散发性人类帕金森症病例中的神经变性。 过表达α-突触核蛋白的转基因小鼠也可能是合适的研究对象。 研究类路易体形成机制和作用的模型 黑质纹状体变性的内含物。最后，研究结果可以提供线索， 这就是为什么老化的黑质纹状体系统变得更容易受到 神经变性