α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons
α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons
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DOI：
10.1126/scitranslmed.3004676
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发表时间：
2012-12-05
影响因子：
17.1
通讯作者：
Bjorklund, Anders
中科院分区：
文献类型：
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作者：
Decressac, Mickael;Kadkhodaei, Banafsheh;Bjorklund, Anders
胶质细胞源性神经营养因子（GDNF）及其近亲neurturin目前正在帕金森病（PD）患者中进行神经保护的临床试验。然而，在PD动物模型中，GDNF未能保护黑质多巴胺（DA）神经元免受α-突触核蛋白诱导的神经变性。使用病毒载体交付的人野生型α-突触核蛋白黑质DA神经元在大鼠中，我们表明，GDNF的细胞内反应被阻断在DA神经元，过表达α-突触核蛋白。这种阻断伴随着转录因子Nurr 1及其下游靶点GDNF受体Ret的表达减少。我们发现PD患者黑质DA神经元的Ret表达也减少。在小鼠中，Nurr 1的条件性敲除导致Ret表达减少和对GDNF的反应阻断，而Nurr 1的过表达恢复了信号传导，提供了黑质DA神经元对α-突触核蛋白毒性的保护。这些结果表明，Nurr 1是神经营养因子信号转导的调节剂，并且是细胞防御α-突触核蛋白毒性的关键参与者。
Glial cell line-derived neurotrophic factor (GDNF) and its close relative neurturin are currently in clinical trials for neuroprotection in patients with Parkinson disease (PD). However, in animal models of PD, GDNF fails to protect nigral dopamine (DA) neurons against alpha-synuclein-induced neurodegeneration. Using viral vector delivery of human wild-type alpha-synuclein to nigral DA neurons in rats, we show that the intracellular response to GDNF is blocked in DA neurons that overexpress alpha-synuclein. This block is accompanied by reduced expression of the transcription factor Nurr1 and its downstream target, the GDNF receptor Ret. We found that Ret expression was also reduced in nigral DA neurons in PD patients. Conditional knockout of Nurr1 in mice resulted in reduced Ret expression and blockade of the response to GDNF, whereas overexpression of Nurr1 restored signaling, providing protection of nigral DA neurons against alpha-synuclein toxicity. These results suggest that Nurr1 is a regulator of neurotrophic factor signaling and a key player in the cellular defense against alpha-synuclein toxicity.