Nat Commun Ji Jing's team discovered a new mechanism for prodynein​ to regulate neuronal death after traumatic brain injury

Editor | TBI (traumatic brain injury) is one of the most fatal and disability diseases in the world, and it also brings a serious social burden [1]
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The secondary injury after TBI is currently considered to be the main reason affecting the prognosis and rehabilitation of patients with traumatic brain injury [2]
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In the research in this field, precision medicine characterized by molecular targeted therapy has become a potential guide for TBI treatment and neurorehabilitation [3, 4]
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However, the current molecular targeted drugs that promote neurorehabilitation are limited by low conversion rates and poor therapeutic effects, and more in-depth research is still needed
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Recently, the team of Professor Ji Jing of Neurosurgery from the First Affiliated Hospital of Nanjing Medical University (Jiangsu Provincial People’s Hospital) published the first paper titled Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury in Nature Communications, and found that the brain After trauma, the feedback of Prokineticin-2 (Prok2) increases, and it is proposed that Prok2 plays an important role in the process of neuronal iron death (ferroptosis) after traumatic brain injury
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At the same time, the role of Prok2-Fbxo10-Acsl4 as a signal axis in inhibiting neuronal iron death and the accompanying lipid peroxidation damage was demonstrated in the neuron stretch model (in vitro brain trauma model)
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The team first performed RNA high-throughput sequencing on the obtained human samples and analyzed the differential gene-Prok2 specifically expressed in neurons
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Through screening of a variety of cell damage and cytotoxic drugs, it is found that Prok2 is more sensitive to toxic drugs related to iron death
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As a new type of death regulation mechanism, iron death is iron-dependent programmed death that is accompanied by lipid peroxidation [5].
The up-regulation of Acsl4, which is representative, is an important factor in the occurrence of iron death [6]
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At the same time, the process of iron death does not depend on the activation of the classic caspase family, nor is it limited to RIP1-RIP3-MLKL-related necroptosis
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Therefore, Prok2, which is sensitive to iron death, may be a potential factor in breaking the bottleneck of neurorehabilitation therapy
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The research innovatively found that in primary neurons, exogenous up-regulation of Prok2 can participate in the process of inhibiting iron death
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In this process, the ubiquitinated ligase Fbxo10, which is up-regulated by Prok2, plays an important role.
Its amino acids 460-867 can specifically bind to the key iron death protein Acsl4, thereby making Acsl4 ubiquitinated and degrading and inhibiting iron death.
(Picture 1)
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The study also verified the effectiveness of Prok2 in reducing neuronal iron death in animal models of craniocerebral trauma
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And observe the recovery of mice after TBI injury by Micro-MRI, which intuitively reflects the brain protection effect of Prok2
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Further behavioral experiments in mice have been conducted to evaluate the efficacy of the Prok2-Fbxo10-Acsl4 regulatory axis in promoting the recovery of sports and cognitive abilities
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Figure 1 In summary, the team revealed the protective effect of Prok2 on neurons after traumatic brain injury, and further explained the importance of the Prok2-Fbxo10-Acsl4 regulatory axis in inhibiting neuronal iron death and the accompanying lipid peroxidation.
It provides a new direction for neurorehabilitation, and provides a strong theoretical basis for the development of molecular targeted drugs for craniocerebral trauma, and provides a new strategy for clinical neurorehabilitation of patients with craniocerebral trauma
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Bao Zhongyuan, a 2021 doctoral student of the First Clinical School of Nanjing Medical University, is the first author, and Professor Ji Jing from the First Affiliated Hospital of Nanjing Medical University and the First Clinical School of Nanjing Medical University is the corresponding author
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