<br>CDK5-USP30信号通路通过抑制MPTP/MPP+ PD模型中的线粒体自噬来调节MAVS介导的炎症,Ecotoxicology and Environmental Safety

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CDK5-USP30信号通路通过抑制MPTP/MPP+ PD模型中的线粒体自噬来调节MAVS介导的炎症
Ecotoxicology and Environmental Safety ( IF 6.2 ) Pub Date : 2024-05-20 , DOI: 10.1016/j.ecoenv.2024.116446
Yixian Ren ₁ , Xian Wu ₂ , Tianyao Bai ₂ , Nanfei Yang ₂ , Yuyu Yuan ₂ , Lingling Xu ₂ , Yue Wen ₂ , Ying Wen ₂ , Zhi Wang ₃ , Liping Zhou ₃ , Fei Zou ₂ , Wenjun Li ₂

Affiliation

MPTP 是一种工业化学品和非法麻醉品污染物，可导致人类、非人类灵长类动物和啮齿类动物患帕金森病，其发现已导致环境污染物暴露被认为是帕金森病 (PD) 发病机制的关键候选者。尽管 MPTP 诱导的线粒体功能障碍和神经炎症是 MPTP 神经毒性的主要原因，但其潜在机制仍不清楚。在这里，我们揭示了 CDK5-USP30-MAVS 调节 MPTP/MPP+ 诱导的 PD 的新信号机制。 MPP+（MPTP 的有毒代谢物）治疗不仅会导致 USP30 蛋白水平升高，还会导致 BV2 小胶质细胞中线粒体自噬抑制、线粒体功能障碍和 MAVS 介导的炎症。在 MPP+ 诱导的细胞模型中，线粒体自噬刺激（尿石素 A 给药）和 USP30 敲低均通过恢复线粒体自噬和线粒体功能来缓解 MAVS 介导的炎症。值得注意的是，MPTP/MPP+诱导的CDK5激活调节USP30丝氨酸216的磷酸化以稳定USP30。此外，CDK5-USP30 通路在 MPTP/MPP+ 诱导的 PD 模型中促进 MAVS 介导的炎症。抑制CDK5不仅可以在体外通过抑制USP30的上调和MAVS炎症通路的激活对MPP+诱导的PD细胞模型产生保护作用，而且可以在体内预防神经变性并减轻MPTP小鼠PD模型的运动障碍。总体而言，我们的研究表明，CDK5 通过磷酸化 USP30 阻断线粒体自噬，并在 MPTP/MPP+ 诱导的 PD 模型中激活 MAVS 炎症通路，这表明 CDK5-USP30-MAVS 信号通路代表了环境神经毒性污染物诱导的 PD 的一种有价值的治疗策略。到 MPTP。

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CDK5-USP30 signaling pathway regulates MAVS-mediated inflammation via suppressing mitophagy in MPTP/MPP+ PD model

The discovery of MPTP, an industrial chemical and contaminant of illicit narcotics, which causes parkinsonism in humans, non-human primates and rodents, has led to environmental pollutants exposure being convicted as key candidate in Parkinson’s disease (PD) pathogenesis. Though MPTP-induced mitochondrial dysfunction and neuroinflammation are mainly responsible for the causative issue of MPTP neurotoxicity, the underlying mechanism involved remains unclear. Here, we reveal a novel signaling mechanism of CDK5-USP30-MAVS regulating MPTP/MPP+ induced PD. MPP+ (the toxic metabolite of MPTP) treatment not only led to the increased protein levels of USP30 but also to mitophagy inhibition, mitochondrial dysfunction, and MAVS-mediated inflammation in BV2 microglial cells. Both mitophagy stimulation (Urolithin A administration) and USP30 knockdown relieved MAVS-mediated inflammation via restoring mitophagy and mitochondrial function in MPP+-induced cell model. Notably, MPTP/MPP+-induced CDK5 activation regulated USP30 phosphorylation at serine 216 to stabilize USP30. Moreover, CDK5-USP30 pathway promoted MAVS-mediated inflammation in MPTP/MPP+-induced PD model. Inhibition of CDK5 not only had a protective effect on MPP+-induced cell model of PD via suppressing the upregulation of USP30 and the activation of MAVS inflammation pathway in vitro, but also prevented neurodegeneration in vivo and alleviated movement impairment in MPTP mouse model of PD. Overall, our study reveal that CDK5 blocks mitophagy through phosphorylating USP30 and activates MAVS inflammation pathway in MPTP/MPP+-induced PD model, which suggests that CDK5-USP30-MAVS signaling pathway represents a valuable treatment strategy for PD induced by environmental neurotoxic pollutants in relation to MPTP.

更新日期：2024-05-20

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