Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
Pro-survival role for Parkinson's associated gene DJ-1 revealed in trophically impaired dopaminergic neurons.
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DOI：
10.1371/journal.pbio.1000349
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发表时间：
2010-04-06
期刊：
影响因子：
9.8
通讯作者：
Klein R
中科院分区：
文献类型：
--
作者：
Aron L;Klein P;Pham TT;Kramer ER;Wurst W;Klein R
一项小鼠遗传研究揭示了帕金森氏病相关基因DJ-1在内源性生存因子支持减少的多巴胺能神经元中的新细胞存活作用。帕金森病（PD）中黑质（SN）神经元选择性死亡的机制尚不清楚。虽然氧化应激抑制因子DJ-1的失活可导致PD，但缺乏DJ-1的动物模型在SN中未显示明显的多巴胺能（DA）神经元变性。在这里，我们发现，与只缺乏Ret信号的小鼠相比，在DA系统中缺乏DJ-1和gdnf受体Ret的衰老小鼠显示SN细胞体的加速损失，而不是轴突的加速损失。DJ-1的生存要求是针对SN中girk2阳性亚群的，该亚群只投射到纹状体，在PD中更脆弱。利用果蝇遗传学，我们发现组成活性的Ret和相关的Ras/ERK，而不是PI3K/Akt，信号成分与DJ-1基因相互作用。双功能丧失实验表明，DJ-1与ERK信号相互作用，控制眼睛和翅膀的发育。我们的研究揭示了DJ-1与ret介导的信号传导之间的保守相互作用，以及DJ-1在小鼠细胞存活中的新作用。更好地了解营养信号，细胞应激和衰老之间的分子联系可以发现PD药物开发的新靶点。帕金森病的主要病理事件是中脑结构黑质中多巴胺能神经元的丢失。家族性帕金森病的研究已经发现了几个与疾病相关的基因，包括DJ-1。随后的研究表明，DJ-1蛋白是氧化应激的抑制因子，可能会改变调节细胞存活的信号通路。然而，由于缺乏DJ-1功能的动物模型未表现出多巴胺能神经变性，因此DJ-1在体内的功能尚不清楚。利用小鼠遗传学，我们发现DJ-1仅在衰老条件下和仅在接受营养信号部分受损的神经元中是黑质神经元存活所必需的。与仅缺乏Ret的衰老小鼠相比，缺乏DJ-1和Ret（一种神经元存活因子受体）的衰老小鼠在黑质中失去更多的多巴胺能神经元。利用果蝇，我们确定DJ-1与构成活性Ret及其相关的下游信号通路相互作用。因此，了解营养信号、细胞应激和衰老之间的分子联系，有助于确定帕金森病药物开发的新靶点。
A mouse genetic study reveals a novel cell-survival role for the Parkinson's disease-associated gene DJ-1 in dopaminergic neurons that have reduced support from endogenous survival factors. The mechanisms underlying the selective death of substantia nigra (SN) neurons in Parkinson disease (PD) remain elusive. While inactivation of DJ-1, an oxidative stress suppressor, causes PD, animal models lacking DJ-1 show no overt dopaminergic (DA) neuron degeneration in the SN. Here, we show that aging mice lacking DJ-1 and the GDNF-receptor Ret in the DA system display an accelerated loss of SN cell bodies, but not axons, compared to mice that only lack Ret signaling. The survival requirement for DJ-1 is specific for the GIRK2-positive subpopulation in the SN which projects exclusively to the striatum and is more vulnerable in PD. Using Drosophila genetics, we show that constitutively active Ret and associated Ras/ERK, but not PI3K/Akt, signaling components interact genetically with DJ-1. Double loss-of-function experiments indicate that DJ-1 interacts with ERK signaling to control eye and wing development. Our study uncovers a conserved interaction between DJ-1 and Ret-mediated signaling and a novel cell survival role for DJ-1 in the mouse. A better understanding of the molecular connections between trophic signaling, cellular stress and aging could uncover new targets for drug development in PD. The major pathological event in Parkinson disease is the loss of dopaminergic neurons in a midbrain structure, the substantia nigra. The study of familial Parkinson disease has uncovered several disease-associated genes, including DJ-1. Subsequent studies have suggested that the DJ-1 protein is a suppressor of oxidative stress that might modify signaling pathways that regulate cell survival. However, because animal models lacking DJ-1 function do not show dopaminergic neurodegeneration, the function(s) of DJ-1 in vivo remain unclear. Using mouse genetics, we found that DJ-1 is required for survival of neurons of the substantia nigra only in aging conditions and only in neurons that are partially impaired in receiving trophic signals. Aging mice that lack DJ-1 and Ret, a receptor for a neuronal survival factor, lose more dopaminergic neurons in the substantia nigra as compared with aging mice that lack only Ret. Using the fruit fly Drosophila, we determined that DJ-1 interacts with constitutively active Ret and with its associated downstream signaling pathways. Therefore, understanding the molecular connections between trophic signaling, cellular stress and aging could facilitate the identification of new targets for drug development in Parkinson Disease.
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影响因子：
7.8
作者：
Heumann, R;Goemans, C;Bartsch, D;Lingenhohl, K;Waldmeier, P C;Hengerer, B;Allegrini, P R;Schellander, K;Wagner, E F;Arendt, T;Kamdem, R H;Obst-Pernberg, K;Narz, F;Wahle, P;Berns, H
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