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Deletion of mammalian sterile 20-like kinase 1 attenuates neuronal loss and improves locomotor function in a mouse model of spinal cord trauma

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Abstract

Neuronal cell death following spinal cord injury (SCI) is an important contributor to neurological deficits. The purpose of our work was to delineate the function of mammalian sterile 20-like kinase 1 (Mst1), a pro-apoptotic kinase and key mediator of apoptotic signaling, in the pathogenesis of an experimental mouse model of SCI. Male mice received a mid-thoracic spinal contusion injury, and it was found that phosphorylation of Mst1 at the injured site was enhanced significantly following SCI. Furthermore, when compared to the wild-type controls, Mst1-deficient mice displayed improved locomotor function by increased Basso mouse scale score. Deletion of Mst1 in mice attenuated loss of motor neurons and suppressed microglial and glial activation following SCI. Deletion of Mst1 in mice reduced apoptosis via suppressing cytochrome c release and caspase-3 activation following SCI. Deletion of Mst1 attenuated mitochondrial dysfunction and increased ATP formation following SCI. Deletion of Mst1 in mice inhibited local inflammation following SCI, evidenced by reduced activities of myeloperoxidase and protein levels of TNF-α, IL-1β, and IL-6. In conclusion, the present study demonstrated that deletion of Mst1 attenuated neuronal loss and improved locomotor function in a mouse model of SCI, via preserving mitochondrial function, attenuating mitochondria-mediated apoptotic pathway, and suppressing inflammation, at least in part.

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Abbreviations

AFU:

Arbitrary fluorescence unit

BMS:

Basso mouse scale

GFAP:

Glial fibrillary acidic protein

IBA1:

Ionized calcium-binding adapter molecule 1

MMP:

Mitochondrial membrane potential

MPO:

Myeloperoxidase

Mst1:

Mammalian sterile 20-like kinase 1

SCI:

Spinal cord injury

TNF-α:

Tumor necrosis factor alpha

WT:

Wild-type mice

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Author contributions

Conception and design of the experiments: P. W., D. X., S. X. Performed the experiments: P. W., D. X., Y. Z., X. L., Y. X., P. Z., Q. F., S. X. Collection, analysis and interpretation of data: P. W., D. X., Y. Z., X. L., Y. X., P. Z., Q. F. Drafting the article: P. W., D. X., S. X.

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    Authors and Affiliations

    1. War and Traumat Emergency Centre, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China

      Pan-feng Wang, Da-yuan Xu, Yuntong Zhang, Xiao-bin Liu, Yan Xia, Pan-yu Zhou, Qing-ge Fu & Shuo-gui Xu

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    1. Pan-feng Wang
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    Correspondence to Shuo-gui Xu.

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    Pan-feng Wang and Da-yuan Xu have equally contributed on this work.

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    Wang, Pf., Xu, Dy., Zhang, Y. et al. Deletion of mammalian sterile 20-like kinase 1 attenuates neuronal loss and improves locomotor function in a mouse model of spinal cord trauma. Mol Cell Biochem 431, 11–20 (2017). https://doi.org/10.1007/s11010-017-2969-1

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