Aix Marseille University, CNRS, IBDM, NeuroMarseille, Marseille, France.
Aix Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France.
Cell Death Dis. 2021 May 8;12(5):460. doi: 10.1038/s41419-021-03742-4.
TP53INP1 is a stress-induced protein, which acts as a dual positive regulator of transcription and of autophagy and whose deficiency has been linked with cancer and metabolic syndrome. Here, we addressed the unexplored role of TP53INP1 and of its Drosophila homolog dDOR in the maintenance of neuronal homeostasis under chronic stress, focusing on dopamine (DA) neurons under normal ageing- and Parkinson's disease (PD)-related context. Trp53inp1 mice displayed additional loss of DA neurons in the substantia nigra compared to wild-type (WT) mice, both with ageing and in a PD model based on targeted overexpression of α-synuclein. Nigral Trp53inp1 expression of WT mice was not significantly modified with ageing but was markedly increased in the PD model. Trp53inp2 expression showed similar evolution and did not differ between WT and Trp53inp1 mice. In Drosophila, pan-neuronal dDOR overexpression improved survival under paraquat exposure and mitigated the progressive locomotor decline and the loss of DA neurons caused by the human α-synuclein A30P variant. dDOR overexpression in DA neurons also rescued the locomotor deficit in flies with RNAi-induced downregulation of dPINK1 or dParkin. Live imaging, confocal and electron microscopy in fat bodies, neurons, and indirect flight muscles showed that dDOR acts as a positive regulator of basal autophagy and mitophagy independently of the PINK1-mediated pathway. Analyses in a mammalian cell model confirmed that modulating TP53INP1 levels does not impact mitochondrial stress-induced PINK1/Parkin-dependent mitophagy. These data provide the first evidence for a neuroprotective role of TP53INP1/dDOR and highlight its involvement in the regulation of autophagy and mitophagy in neurons.
TP53INP1 是一种应激诱导蛋白，作为转录和自噬的双重正调节剂，其缺失与癌症和代谢综合征有关。在这里，我们研究了 TP53INP1 及其果蝇同源物 dDOR 在慢性应激下维持神经元内稳态的未知作用，重点关注正常衰老和帕金森病（PD）相关背景下的多巴胺（DA）神经元。与野生型（WT）小鼠相比，Trp53inp1 小鼠在黑质中显示出更多的 DA 神经元丢失，无论是在衰老过程中还是在基于α-突触核蛋白靶向过表达的 PD 模型中。WT 小鼠黑质中的 Trp53inp1 表达随衰老没有明显变化，但在 PD 模型中明显增加。Trp53inp2 表达表现出相似的变化，WT 和 Trp53inp1 小鼠之间没有差异。在果蝇中，pan-neuronal dDOR 过表达可改善百草枯暴露下的存活率，并减轻人类α-突触核蛋白 A30P 变体引起的进行性运动减退和 DA 神经元丢失。DA 神经元中 dDOR 的过表达也挽救了 RNAi 下调 dPINK1 或 dParkin 后果蝇的运动缺陷。在脂肪体、神经元和间接飞行肌肉中的活体成像、共聚焦和电子显微镜分析表明，dDOR 作为一种独立于 PINK1 介导途径的基础自噬和 mitophagy 的正调节剂发挥作用。在哺乳动物细胞模型中的分析证实，调节 TP53INP1 水平不会影响线粒体应激诱导的 PINK1/Parkin 依赖性 mitophagy。这些数据首次为 TP53INP1/dDOR 的神经保护作用提供了证据，并强调了其在神经元自噬和 mitophagy 调节中的作用。
