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MIF promotes neurodegeneration and cell death via its nuclease activity following traumatic brain injury

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Abstract

Traumatic brain injury (TBI), often induced by sports, car accidents, falls, or other daily occurrences, is a primary non-genetically related risk factor for the development of subsequent neurodegeneration and neuronal cell death. However, the molecular mechanisms underlying neurodegeneration, cell death, and neurobehavioral dysfunction following TBI remain unclear. Here, we found that poly(ADP-ribose) polymerase-1 (PARP-1) was hyperactivated following TBI and its inhibition reduced TBI-induced brain injury. Macrophage migration inhibitory factor (MIF), a newly identified nuclease involved in PARP-1-dependent cell death, was translocated from the cytosol to the nucleus in cortical neurons following TBI and promoted neuronal cell death in vivo. Genetic deletion of MIF protected neurons from TBI-induced dendritic spine loss, morphological complexity degeneration, and subsequent neuronal cell death in mice. Moreover, MIF knockout reduced the brain injury volume and improved long-term animal behavioral rehabilitation. These neuroprotective effects in MIF knockout mice were reversed by the expression of wild-type MIF but not nuclease-deficient MIF mutant. In contrast, genetic deletion of MIF did not alter TBI-induced neuroinflammation. These findings reveal that MIF mediates TBI-induced neurodegeneration, neuronal cell death and neurobehavioral dysfunction through its nuclease activity, but not its pro-inflammatory role. Targeting MIF’s nuclease activity may offer a novel strategy to protect neurons from TBI.

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Acknowledgements

We thank Dr. W. Lee Kraus for providing PARP-1 KO mice and the UT Southwestern Medical Center Next Generation Sequencing Core for assistance with RNA-Seq.

Funding

This work was supported by grants from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke R00NS078049, National Institute of General Medical Sciences R35GM124693, and National Institute on Aging R01AG066166, Darrell K Royal Research Fund (DKR), Welch Foundation (I-1939-20170325), CPRIT-HIHR RP170671, TIBIR pilot Grant, the University of Texas (UT) Southwestern Medical Center Startup funds and UT Rising Stars to Y.W., and the Welch Foundation I-1903-20190330 to W.L.

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Author notes

  1. Qing Lu

    Present address: Department of Pharmacology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

  2. Zhi Ruan, Qing Lu and Jennifer E. Wang contributed equally.

Authors and Affiliations

  1. Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Zhi Ruan, Qing Lu, Jennifer E. Wang, Mi Zhou, Shuiqiao Liu, Hongxia Zhang, Akshay Durvasula, Yijie Wang, Yanan Wang, Weibo Luo & Yingfei Wang

  2. Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Weibo Luo

  3. Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Yingfei Wang

  4. Peter O’Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA

    Yingfei Wang

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  1. Zhi Ruan
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Contributions

YW and WL conceived the idea, designed research, analyzed data and wrote the paper. ZR initiated the project and performed the majority of the experiments including TBI surgery, Nissl staining, Golgi staining, and neuron morphology tracing and analysis. QL continued the project and performed TBI surgery, Nissl staining, Golgi staining, and neuron morphology tracing and analysis. JEW maintained the mouse lines and performed mouse genotyping, TBI surgery on both MIF and PARP mice, and animal behavioral tests. MZ performed mRNA sequencing studies. SL performed FJC and microglial activation experiments. HZ performed PARP inhibitor injection study. AD contributed to the blind animal behavior data analysis. YJW performed MIF western blots. YNW performed PARP-1 KO western blots. All authors read and approved the final manuscript.

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Correspondence to Yingfei Wang.

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Ruan, Z., Lu, Q., Wang, J.E. et al. MIF promotes neurodegeneration and cell death via its nuclease activity following traumatic brain injury. Cell. Mol. Life Sci. 79, 39 (2022). https://doi.org/10.1007/s00018-021-04037-9

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