MPTP的发现,一种工业化学品和非法麻醉品污染物,导致人类帕金森病,非人灵长类动物和啮齿动物,导致环境污染物暴露被定罪为帕金森病(PD)发病机制的关键候选人。尽管MPTP诱导的线粒体功能障碍和神经炎症是引起MPTP神经毒性的主要原因,所涉及的潜在机制尚不清楚.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的毒性代谢产物)治疗不仅导致USP30的蛋白质水平增加,而且导致线粒体自噬抑制,线粒体功能障碍,和MAVS介导的BV2小胶质细胞炎症。在MPP+诱导的细胞模型中,线粒体自噬刺激(尿蛋白A给药)和USP30敲低都通过恢复线粒体自噬和线粒体功能缓解了MAVS介导的炎症。值得注意的是,MPTP/MPP+诱导的CDK5活化调节USP30在丝氨酸216处的磷酸化以稳定USP30。此外,CDK5-USP30通路促进MPTP/MPP+诱导的PD模型中MAVS介导的炎症反应。抑制CDK5不仅在体外抑制USP30的上调和MAVS炎症通路的激活,对MPP+诱导的PD细胞模型具有保护作用,而且还可以预防体内神经变性并减轻PDMPTP小鼠模型的运动障碍。总的来说,我们的研究表明,在MPTP/MPP+诱导的PD模型中,CDK5通过磷酸化USP30阻断线粒体自噬并激活MAVS炎症通路,这表明CDK5-USP30-MAVS信号通路代表了与MPTP相关的环境神经毒性污染物诱导的PD的有价值的治疗策略。
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.