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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.
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Dopaminergic neuronal loss in transgenic mice expressing the Parkinson's disease-associated UCH-L1 I93M mutant.

机译：表达帕金森氏病相关UCH-L1 I93M突变体的转基因小鼠的多巴胺能神经元丢失。

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摘要

The I93M mutation in ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) was reported in one German family with autosomal dominant Parkinson's disease (PD). The causative role of the mutation has, however, been questioned. We generated transgenic (Tg) mice carrying human UCHL1 under control of the PDGF-B promoter; two independent lines were generated with the I93M mutation (a high- and low-expressing line) and one line with wild-type human UCH-L1. We found a significant reduction in the dopaminergic neurons in the substantia nigra and the dopamine content in the striatum in the high-expressing I93M Tg mice as compared with non-Tg mice at 20 weeks of age. Although these changes were absent in the low-expressing I93M Tg mice, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment profoundly reduced dopaminergic neurons in this line as compared with wild-type Tg or non-Tg mice. Abnormal neuropathologies were also observed, such as silver staining-positive argyrophilic grains in the perikarya of degenerating dopaminergic neurons, in I93M Tg mice. The midbrains of I93M Tg mice contained increased amounts of insoluble UCH-L1 as compared with those of non-Tg mice, perhaps resulting in a toxic gain of function. Collectively, our data represent in vivo evidence that expression of UCHL1(I93M) leads to the degeneration of dopaminergic neurons.
机译：在一个常染色体显性遗传性帕金森氏病（PD）的德国家庭中，泛素羧基末端水解酶L1（UCH-L1）发生了I93M突变。然而，该突变的致病作用受到质疑。我们在PDGF-B启动子的控制下产生了携带人UCHL1的转基因（Tg）小鼠;产生了两个具有I93M突变的独立品系（一个高表达和低表达品系），一个具有野生型人UCH-L1的品系。我们发现与20周龄的非Tg小鼠相比，高表达I93M Tg小鼠的黑质中的多巴胺能神经元和纹状体中的多巴胺含量显着减少。尽管在低表达I93M Tg小鼠中没有这些变化，但是与野生型Tg或野生型Tg相比，1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理可显着减少该系中的多巴胺能神经元。非Tg小鼠。还观察到异常的神经病理学，例如在I93M Tg小鼠中，退化的多巴胺能神经元周围核中的银染阳性嗜银粒。与非Tg小鼠相比，I93M Tg小鼠的中脑含有增加量的不溶性UCH-L1，这可能导致功能性毒性增加。总的来说，我们的数据代表了UCHL1（I93M）表达导致多巴胺能神经元变性的体内证据。

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