Conditional expression of Parkinson's disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1.
Conditional expression of Parkinson's disease-related mutant α-synuclein in the midbrain dopaminergic neurons causes progressive neurodegeneration and degradation of transcription factor nuclear receptor related 1.
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中脑多巴胺能神经元中与帕金森氏病相关的突变体α-突触核蛋白的有条件表达会导致进行性神经变性和转录因子核受体相关的降解1。
DOI：
10.1523/jneurosci.1731-12.2012
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发表时间：
2012-07-04
期刊：
影响因子：
--
通讯作者：
Cai H
中科院分区：
文献类型：
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作者：
Lin X;Parisiadou L;Sgobio C;Liu G;Yu J;Sun L;Shim H;Gu XL;Luo J;Long CX;Ding J;Mateo Y;Sullivan PH;Wu LG;Goldstein DS;Lovinger D;Cai H
α-突触核蛋白（α-syn）在帕金森病（PD）中脑多巴胺能（mDA）神经元退行性变中起重要作用。然而，体内对mDA神经元α-syn的研究很少，这可能是由于缺乏α-syn转基因小鼠出现pd样的mDA神经元严重变性所致。为了深入了解α-syn诱导的mDA神经变性的机制，我们在mDA神经元中建立了一个新的四环素调节诱导转基因小鼠，该小鼠在pd相关的α-syn A53T错义突变中过表达。在这里，我们发现突变小鼠出现了严重的运动障碍和强大的mDA神经变性，类似于PD的一些关键运动和病理表型。我们进一步系统地检查了突变小鼠mDA神经元中出现的亚细胞异常，并观察到这些神经元中多巴胺释放明显减少，高尔基体断裂，自噬/溶酶体降解途径受损。为了进一步了解导致mDA神经元α-syn依赖变性的具体分子事件，我们发现α-syn的过表达促进了蛋白酶体依赖的核受体相关1蛋白（Nurr1）的降解；而抑制Nurr1降解可改善α-syn诱导的mDA神经元丢失。鉴于Nurr1在维持mDA神经元的正常功能和存活中起着至关重要的作用，我们的研究提示α-syn介导的Nurr1蛋白表达的抑制可能是mDA神经元在PD发病过程中优先易感性的原因之一。
α-synuclein(α-syn) plays a prominent role in the degeneration of midbrain dopaminergic (mDA) neurons in Parkinson disease (PD). However, only a few studies on α-syn have been carried out in the mDA neurons in vivo, which may be attributed to a lack of α-syn transgenic mice that develop PD-like severe degeneration of mDA neurons. To gain mechanistic insights into the α-syn-induced mDA neurodegeneration, we generated a new line of tetracycline-regulated inducible transgenic mice that overexpressed the PD-related α-syn A53T missense mutation in the mDA neurons. Here we show that the mutant mice developed profound motor disabilities and robust mDA neurodegeneration, resembling some key motor and pathological phenotypes of PD. We further systematically examined the subcellular abnormalities appeared in the mDA neurons of mutant mice, and observed a profound decrease of dopamine release, the fragmentation of Golgi apparatus, and impairments of autophagy/lysosome degradation pathways in these neurons. To further understand the specific molecular events leading to the α-syn-dependent degeneration of mDA neurons, we found that over-expression of α-syn promoted a proteasome-dependent degradation of nuclear receptor related 1 protein (Nurr1); while inhibition of Nurr1 degradation ameliorated the α-syn-induced loss of mDA neurons. Given that Nurr1 plays an essential role in maintaining the normal function and survival of mDA neurons, our studies suggest that the α-syn-mediated suppression of Nurr1 protein expression may contribute to the preferential vulnerability of mDA neurons in the pathogenesis of PD.