Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury

Zhongyuan Bao, Yinlong Liu, Binglin Chen, Zong Miao, Yiming Tu, Chong Li, Honglu Chao, Yangfan Ye, Xiupeng Xu, Guangchi Sun, Pengzhan Zhao, Ning Liu, Yan Liu, Xiaoming Wang, Sin Man Lam, Valerian E. Kagan, Hülya Bayır and Jing Ji ()
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Zhongyuan Bao: the First Affiliated Hospital of Nanjing Medical University
Yinlong Liu: the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital
Binglin Chen: the First Affiliated Hospital of Nanjing Medical University
Zong Miao: the First Affiliated Hospital of Nanjing Medical University
Yiming Tu: the First Affiliated Hospital of Nanjing Medical University
Chong Li: the First Affiliated Hospital of Nanjing Medical University
Honglu Chao: the First Affiliated Hospital of Nanjing Medical University
Yangfan Ye: the First Affiliated Hospital of Nanjing Medical University
Xiupeng Xu: the First Affiliated Hospital of Nanjing Medical University
Guangchi Sun: the First Affiliated Hospital of Nanjing Medical University
Pengzhan Zhao: the First Affiliated Hospital of Nanjing Medical University
Ning Liu: the First Affiliated Hospital of Nanjing Medical University
Yan Liu: Nanjing Medical University
Xiaoming Wang: Nanjing Medical University
Sin Man Lam: LipidALL Technologies Company Limited
Valerian E. Kagan: University of Pittsburgh
Hülya Bayır: University of Pittsburgh
Jing Ji: the First Affiliated Hospital of Nanjing Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24469-y

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