The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models
The STING pathway does not contribute to behavioural or mitochondrial phenotypes in Drosophila Pink1/parkin or mtDNA mutator models
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DOI：
10.1038/s41598-020-59647-3
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发表时间：
2020-02-14
影响因子：
4.6
通讯作者：
Whitworth, Alexander J.
中科院分区：
文献类型：
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作者：
Lee, Juliette J.;Andreazza, Simonetta;Whitworth, Alexander J.
PINK1和Parkin/PRKN基因突变导致家族性帕金森病的多巴胺能神经元变性，但确切的发病机制尚不清楚。PINK1/Parkin通路被描述为通过信号对受损线粒体的靶向破坏在线粒体动态平衡中发挥核心作用，然而，直到最近，破坏这一过程如何导致神经元死亡还不清楚。在小鼠身上进行的一项优雅的研究表明，PINK1或PRKN的丢失加上额外的线粒体应激导致先天性免疫信号的异常激活，这种信号通过cGAS/STIN途径介导，导致多巴胺能神经元退化和运动障碍。Sting的基因敲除足以完全防止神经变性和伴随的运动障碍。为了确定Sting在PINK1/Parkin相关的病理中是否起到保守的作用，我们在果蝇中测试了Sting和PINK1/Parkin之间的遗传相互作用。令人惊讶的是，我们发现Sting的丢失或其下游效应器的味道，不足以抑制PINK1/parkin突变体中的行为缺陷或线粒体破坏。因此，我们得出结论，与PINK1/Parkin丢失相关的表型并不普遍是由于刺痛通路的异常激活。
Mutations in PINK1 and Parkin/PRKN cause the degeneration of dopaminergic neurons in familial forms of Parkinson's disease but the precise pathogenic mechanisms are unknown. The PINK1/Parkin pathway has been described to play a central role in mitochondrial homeostasis by signalling the targeted destruction of damaged mitochondria, however, how disrupting this process leads to neuronal death was unclear until recently. An elegant study in mice revealed that the loss of Pink1 or Prkn coupled with an additional mitochondrial stress resulted in the aberrant activation of the innate immune signalling, mediated via the cGAS/STING pathway, causing degeneration of dopaminergic neurons and motor impairment. Genetic knockout of Sting was sufficient to completely prevent neurodegeneration and accompanying motor deficits. To determine whether Sting plays a conserved role in Pink1/parkin related pathology, we tested for genetic interactions between Sting and Pink1/parkin in Drosophila. Surprisingly, we found that loss of Sting, or its downstream effector Relish, was insufficient to suppress the behavioural deficits or mitochondria disruption in the Pink1/parkin mutants. Thus, we conclude that phenotypes associated with loss of Pink1/parkin are not universally due to aberrant activation of the STING pathway.