DJ-1 knockout augments disease severity and shortens survival in a mouse model of ALS.
DJ-1 knockout augments disease severity and shortens survival in a mouse model of ALS.
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DOI：
10.1371/journal.pone.0117190
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Offen D
中科院分区：
文献类型：
--
作者：
Lev N;Barhum Y;Lotan I;Steiner I;Offen D
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种进行性、致死性、神经退行性疾病，以运动神经元变性为特征。氧化应激在疾病进展中起核心作用，与增强的谷氨酸兴奋毒性和神经炎症一致。DJ-1突变导致功能蛋白的丧失，导致家族性帕金森病和运动神经元病。DJ-1响应氧化应激，并在细胞防御机制中发挥重要作用。我们的目的是研究功能性DJ-1的丧失是否会改变ALS小鼠模型的病程和严重程度。为此，我们使用表达人SOD 1G 93 A突变的小鼠，ALS的常用模型和DJ-1小鼠的敲除以产生SOD 1 DJ-1 KO小鼠。我们发现，在ALS模型中敲除DJ-1导致疾病进程加速和生存时间缩短。发现DJ-1缺乏增加脊髓中的神经元损失，其与脊髓中增加的神经胶质增生和减少的由Nrf 2机制调节的抗氧化反应相关。DJ-1在ALS中的重要性也在暴露于谷氨酸毒性和氧化应激的运动神经元细胞系中得到说明。添加DJ-1衍生肽ND-13增强了对谷氨酸和SIN-1诱导的毒性的抗性。因此，我们的研究结果表明DJ-1在疾病过程中发挥作用，并促进了进一步研究DJ-1作为ALS治疗靶点的必要性。
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal, neurodegenerative disorder, characterized by the degeneration of motor neurons. Oxidative stress plays a central role in the disease progression, in concert with an enhanced glutamate excitotoxicity and neuroinflammation. DJ-1 mutations, leading to the loss of functional protein, cause familial Parkinson’s disease and motor neuron disease in several patients. DJ-1 responds to oxidative stress and plays an important role in the cellular defense mechanisms. We aimed to investigate whether loss of functional DJ-1 alters the disease course and severity in an ALS mouse model. To this end we used mice that express the human SOD1G93A mutation, the commonly used model of ALS and knockout of DJ-1 mice to generate SOD1 DJ-1 KO mice. We found that knocking out DJ-1in the ALS model led to an accelerated disease course and shortened survival time. DJ-1 deficiency was found to increase neuronal loss in the spinal cord associated with increased gliosis in the spinal cord and reduced antioxidant response that was regulated by the Nrf2 mechanism.The importance of DJ-1 in ALS was also illustrated in a motor neuron cell line that was exposed to glutamate toxicity and oxidative stress. Addition of the DJ-1 derived peptide, ND-13, enhanced the resistance to glutamate and SIN-1 induced toxicity. Thus, our results maintain that DJ-1 plays a role in the disease process and promotes the necessity of further investigation of DJ-1 as a therapeutic target for ALS.
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影响因子：
2.9
作者：
Badera, V;Zhu, XR;Stichel, CC
通讯作者：
Stichel, CC
影响因子：
3.1
作者：
Lev, Nirit;Ickowicz, Debby;Offen, Daniel
通讯作者：
Offen, Daniel
DOI：
10.1093/gerona/gls147
发表时间：
2013-03-01
影响因子：
5.1
作者：
Lev, Nirit;Barhum, Yael;Offen, Daniel
通讯作者：
Offen, Daniel
影响因子：
11.2
作者：
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通讯作者：
Brown, RH
影响因子：
6
作者：
Gurney, ME
通讯作者：
Gurney, ME