The mouse MPTP model:: gene expression changes in dopaminergic neurons
The mouse MPTP model:: gene expression changes in dopaminergic neurons
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DOI：
10.1046/j.1460-9568.2003.02408.x
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发表时间：
2003-01-01
影响因子：
3.4
通讯作者：
Stichel, CC
中科院分区：
文献类型：
--
作者：
Kühn, K;Wellen, J;Stichel, CC
帕金森病（PD）是一种常见的神经退行性疾病，其特征是黑质中多巴胺能神经元的进行性丧失。尽管已经开发出有价值的动物模型，但我们对帕金森病的病因和致病因素的了解仍然不足以制定旨在阻止其进展的因果治疗策略。 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 诱导的神经毒性是分析 PD 病理方面最有价值的模型之一。在本文中，我们研究了 MPTP 诱导的神经变性发病机制背后的基因表达模式。我们用不同的 MPTP 方案治疗年轻和年老的 C57BL/6 小鼠，以诱导强度和时间进程不同的退行性过程。在中毒后的第一周，我们使用非放射性原位杂交来研究与（i）多巴胺代谢和信号传导相关的基因的表达模式； (ii) 家族性帕金森病； (iii) 蛋白质折叠和 (iv) 能量代谢。 MPTP 注射会引起不同严重程度的神经元损伤，具体取决于动物的年龄和给药时间表，以及纹状体的显着变性。原位杂交表明，MPTP 中毒引发了许多基因表达变化，这些变化（i）仅限于黑质致密部的神经元； (ii) 变化的强度和数量与动物年龄和组织病理学紊乱的严重程度相关； (iii) 在最后一次 MPTP 注射后一周结束时，每种药物均显示出显着下调，但 (iv) 在观察期间，一个 MPTP 方案中的表达水平有所不同。对一岁小鼠进行亚急性注射 MPTP 会引起最严重的基因表达变化。所有研究的基因都受到影响。然而，α-突触核蛋白是唯一在 MPTP 处理的动物中表现出细胞死亡的上调基因。
Parkinson's disease (PD) is a common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Although valuable animal models have been developed, our knowledge of the aetiology and pathogenic factors implicated in PD is still insufficient to develop causal therapeutic strategies aimed at halting its progression. The neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most valuable models for analysing pathological aspects of PD. In this paper we studied the gene expression patterns underlying the pathogenesis of MPTP-induced neurodegeneration. We treated young and old C57BL/6 mice with different schedules of MPTP to induce degenerative processes that vary in intensity and time-course. During the first week after intoxication we used nonradioactive in situ -hybridization to investigate the expression patterns of genes associated with (i) dopamine metabolism and signalling; (ii) familial forms of PD; (iii) protein folding and (iv) energy metabolism. MPTP injections induced different severities of neuronal injury depending on the age of the animals and the schedule of administration as well as a significant degeneration in the striatum. In situ hybridization showed that MPTP intoxication initiated a number of gene expression changes that (i) were restricted to the neurons of the substantia nigra pars compacta; (ii) were correlated in intensity and number of changes with the age of the animals and the severity of histopathological disturbances; (iii) displayed in each a significant down-regulation by the end of one week after the last MPTP injection, but (iv) varied within one MPTP regimen in expression levels during the observation period. The subacute injection of MPTP into one-year-old mice induced the most severe changes in gene expression. All genes investigated were affected. However, alpha-synuclein was the only gene that was exclusively up-regulated in MPTP-treated animals displaying cell death.