Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 79, Issue 1, Pages -Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-04037-9
Keywords
MIF; Traumatic brain injury; Neurodegeneration; Cell death
Categories
Funding
- National Institutes of Health (NIH)
- National Institute of Neurological Disorders and Stroke [R00NS078049]
- National Institute of General Medical Sciences [R35GM124693]
- National Institute on Aging [R01AG066166]
- Darrell K Royal Research Fund (DKR)
- Welch Foundation [I-1939-20170325, I-1903-20190330]
- CPRIT-HIHR [RP170671]
- TIBIR pilot Grant
- University of Texas (UT) Southwestern Medical Center Startup funds
- UT Rising Stars
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The study found 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.
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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