Department of Neurosurgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Department of Neurosurgery, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou, China.
Nat Commun. 2021 Jul 9;12(1):4220. doi: 10.1038/s41467-021-24469-y.
Prokineticin-2 (Prok2) is an important secreted protein likely involved in the pathogenesis of several acute and chronic neurological diseases through currently unidentified regulatory mechanisms. The initial mechanical injury of neurons by traumatic brain injury triggers multiple secondary responses including various cell death programs. One of these is ferroptosis, which is associated with dysregulation of iron and thiols and culminates in fatal lipid peroxidation. Here, we explore the regulatory role of Prok2 in neuronal ferroptosis in vitro and in vivo. We show that Prok2 prevents neuronal cell death by suppressing the biosynthesis of lipid peroxidation substrates, arachidonic acid-phospholipids, via accelerated F-box only protein 10 (Fbxo10)-driven ubiquitination, degradation of long-chain-fatty-acid-CoA ligase 4 (Acsl4), and inhibition of lipid peroxidation. Mice injected with adeno-associated virus-Prok2 before controlled cortical impact injury show reduced neuronal degeneration and improved motor and cognitive functions, which could be inhibited by Fbxo10 knockdown. Our study shows that Prok2 mediates neuronal cell deaths in traumatic brain injury via ferroptosis.
原癌基因蛋白 2（Prok2）是一种重要的分泌蛋白，可能通过目前尚未明确的调节机制参与多种急性和慢性神经疾病的发病机制。创伤性脑损伤最初对神经元造成的机械损伤会引发多种继发性反应，包括各种细胞死亡程序。其中之一是铁死亡，它与铁和硫醇的失调有关，并最终导致致命的脂质过氧化。在这里，我们探讨了 Prok2 在体外和体内神经元铁死亡中的调节作用。我们发现 Prok2 通过加速 F-box 仅蛋白 10（Fbxo10）驱动的泛素化、长链脂肪酸辅酶 A 连接酶 4（Acsl4）的降解以及抑制脂质过氧化，抑制脂质过氧化产物，花生四烯酸磷脂的生物合成，从而防止神经元细胞死亡。在皮质撞击损伤前注射腺相关病毒-Prok2 的小鼠显示神经元退化减少，运动和认知功能改善，而 Fbxo10 的敲低可抑制这些作用。我们的研究表明，Prok2 通过铁死亡介导创伤性脑损伤中的神经元细胞死亡。
