SYNUCLEIN AGGREGATION AND NEURODEGENATION IN TRANSGENICS

描述：(逐字摘自申请人的摘要)之间的关系 α-突触核蛋白、路易体样包涵体和黑质纹状体变性意志 使用转基因小鼠进行评估，在转基因小鼠中，人类野生型或突变体 (A53T)形式的α-突触核蛋白在酪氨酸作用下过度表达 羟基酶启动子。第一个需要检验的假设是过度表达 人类α-突触核蛋白本身会导致神经退行性变化。中的更改 黑质内多巴胺能神经元的数量变化 纹状体多巴胺能终末与类路易体的可能形成 将在过度表达的小鼠和不同基因的对照组中比较包涵体。 年龄。第二个假设是α-突触核蛋白的过度表达增加 黑质纹状体系统对神经毒性损伤的脆弱性。老鼠会成为 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形成 假说是蛋白酶体活性受损在 α-突触核蛋白聚集和随之而来的神经变性。的影响 蛋白酶体抑制路易体样包涵体的形成 在高表达α-突触核蛋白的小鼠和不高表达的对照组中的比较 在存在和不存在神经毒性暴露的情况下。这些措施的结果 实验应有助于阐明α-突触核蛋白诱导的机制 家族性和散发性人类帕金森综合征患者的神经变性。 过度表达α-突触核蛋白的转基因小鼠也可能是一种合适的 研究类路易体形成机制和作用的模型 黑质纹状体变性中的包裹体。最后，调查结果可能会提供线索 S谈到为什么老化的黑质纹状体系统更容易患上 神经退行性变。

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.