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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals
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RET signaling does not modulate MPTP toxicity but is required for regeneration of dopaminergic axon terminals

机译：RET信号传导不会调节MPTP毒性，但对于多巴胺能轴突末端的再生是必需的

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摘要

Activation of the RET (rearranged during transfection) receptor by glial cell-line-derived neurotrophic factor (GDNF) has been identified as an important differentiation and survival factor for dopaminergic neurons of the midbrain in preclinical experiments. These encouraging results have led to clinical trials of GDNF in patients with Parkinson's disease, which have resulted in conflicting findings. To investigate the potential benefit of Ret-dependent signaling on the challenged dopaminergic system, we tested the effect of tissue-selective ablation of the Ret gene on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice, the most widely used animal model for Parkinson's disease. Ablation of Ret did not modify the MPTP-induced loss of dopaminergic neurons in the substantia nigra pars compacta and the dopaminergic innervation of the striatum at 14 days. However, Ret ablation abolished the regeneration of dopaminergic fibers and terminals, as well as the partial recovery of striatal dopamine concentrations, that was observed in control mice between days 14 and 90 after MPTP treatment. We therefore conclude that RET signaling has no influence on the survival of dopaminergic neurons in the MPTP model of Parkinson's disease but rather facilitates the regeneration of dopaminergic axon terminals.
机译：在临床前实验中，胶质细胞源性神经营养因子（GDNF）激活RET（转染过程中重排）受体的激活是中脑多巴胺能神经元的重要分化和存活因子。这些令人鼓舞的结果导致了在帕金森氏病患者中进行GDNF的临床试验，这导致了相互矛盾的发现。为了研究Ret依赖性信号传导对受挑战的多巴胺能系统的潜在益处，我们测试了Ret基因的组织选择性消融对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的影响对小鼠的毒性，帕金森氏病是使用最广泛的动物模型。 Ret的消融并没有改变MPTP诱导的黑质致密部中多巴胺能神经元的丢失以及纹状体在14天时的多巴胺能神经支配。然而，Ret消融消除了多巴胺能纤维和末端的再生，以及纹状体多巴胺浓度的部分恢复，这在MPTP处理后第14天到第90天之间在对照组小鼠中观察到。因此，我们得出结论，在帕金森氏病的MPTP模型中，RET信号传导对多巴胺能神经元的存活没有影响，而是促进了多巴胺能轴突末端的再生。

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