DJ-1 inhibits microglial activation and protects dopaminergic neurons in vitro and in vivo through interacting with microglial p65.
DJ-1 inhibits microglial activation and protects dopaminergic neurons in vitro and in vivo through interacting with microglial p65.
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DJ-1 通过与小胶质细胞 p65 相互作用抑制小胶质细胞活化并在体外和体内保护多巴胺能神经元
DOI：
10.1038/s41419-021-04002-1
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发表时间：
2021-07-17
影响因子：
9
通讯作者：
Ren H
中科院分区：
文献类型：
--
作者：
Lin Z;Chen C;Yang D;Ding J;Wang G;Ren H
帕金森病（Parkinson's disease，PD）是最常见的神经退行性疾病之一，以黑质多巴胺能神经元的进行性变性为特征。DJ-1在神经元保护和抗神经炎症反应中起重要作用，其功能丧失与家族性隐性形式的PD密切相关。然而，DJ-1参与神经炎症的分子机制在很大程度上还不清楚。在此，我们发现野生型DJ-1，而不是致病性L166 P突变体DJ-1，直接结合细胞质中核因子-κB（NF-κB）的亚基p65，并且DJ-1的缺失通过促进p65和NF-κB抑制剂α（IκBα）之间的解离促进p65核转位。与野生型同窝对照相比，DJ-1敲除（DJ-1−/−）小鼠表现出更多的小胶质细胞活化，特别是在对脂多糖（LPS）治疗的反应中。在细胞模型中，DJ-1的敲低显著上调基因表达并增加原代小胶质细胞和BV 2细胞中LPS处理的炎性细胞因子的释放。此外，小胶质细胞中的DJ-1缺陷显著增强了响应于LPS刺激的神经元毒性。此外，SN-50通过阻断NF-κB核转位，可抑制小胶质细胞的活化，减轻DJ-1缺乏对DA神经元的损伤。因此，我们的数据说明了一种新的机制，DJ-1通过与小胶质细胞中的p65结合，促进IκBα和p65之间的相互作用，从而抑制小胶质细胞活化，并表现出对PD中神经炎症介导的DA神经元损伤的保护作用。
Parkinson’s disease (PD), one of the most common neurodegenerative disorders, is characterized by progressive neurodegeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). DJ-1 acts essential roles in neuronal protection and anti-neuroinflammatory response, and its loss of function is tightly associated with a familial recessive form of PD. However, the molecular mechanism of DJ-1 involved in neuroinflammation is largely unclear. Here, we found that wild-type DJ-1, rather than the pathogenic L166P mutant DJ-1, directly binds to the subunit p65 of nuclear factor-κB (NF-κB) in the cytoplasm, and loss of DJ-1 promotes p65 nuclear translocation by facilitating the dissociation between p65 and NF-κB inhibitor α (IκBα). DJ-1 knockout (DJ-1−/−) mice exhibit more microglial activation compared with wild-type littermate controls, especially in response to lipopolysaccharide (LPS) treatment. In cellular models, knockdown of DJ-1 significantly upregulates the gene expression and increases the release of LPS-treated inflammatory cytokines in primary microglia and BV2 cells. Furthermore, DJ-1 deficiency in microglia significantly enhances the neuronal toxicity in response to LPS stimulus. In addition, pharmacological blockage of NF-κB nuclear translocation by SN-50 prevents microglial activation and alleviates the damage of DA neurons induced by microglial DJ-1 deficiency in vivo and in vitro. Thus, our data illustrate a novel mechanism by which DJ-1 facilitates the interaction between IκBα and p65 by binding to p65 in microglia, and thus repressing microglial activation and exhibiting the protection of DA neurons from neuroinflammation-mediated injury in PD.
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影响因子：
56.9
作者：
Bonifati, V;Rizzu, P;Heutink, P
通讯作者：
Heutink, P
影响因子：
7.2
作者：
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作者：
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6.1
作者：
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影响因子：
11.2
作者：
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通讯作者：
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