Zipper-interacting protein kinase mediates neuronal cell death and cognitive dysfunction in traumatic brain injury via regulating DEDD DOI Creative Commons

Yingxue Mei,

Fei She,

Ling Zhang

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 4, 2025

Abstract Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, upstream trigger TBI-induced neuronal loss underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated Alzheimer’s disease ischemic stroke play role cellular apoptosis, while its pathological significance TBI not reported. Herein, we discovered for first time that ZIPK expression was markedly elevated neurons after caused massive apoptosis peri-contusional regions. Zipk haploinsufficiency antagonized reversed several typical neuropathological changes induced by TBI. Mechanistically, found affected viability modulating effector domain-containing DNA binding (DEDD) caspase-3 pathway. Specifically, could bind phosphorylate DEDD at S9 residue, thus enhancing stability DEDD, leading activation caspase-3-mediated apoptotic cascade neurons. The rescue downregulation effectively alleviated behavioral deficits preserving motor cognitive abilities vivo, supporting decisive dysregulation TBI-associated dysfunctions survival. Furthermore, pharmacological suppression activity specific inhibitor prior protected from injury-induced degeneration vitro vivo preventing upregulation activation. In conclusion, our data reveal essential contribution through DEDD/caspase-3 cascade, suggest potential targeting as an effective strategy treating TBI-related neuropathologies.

Language: Английский

Zipper-interacting protein kinase mediates neuronal cell death and cognitive dysfunction in traumatic brain injury via regulating DEDD DOI Creative Commons

Yingxue Mei,

Fei She,

Ling Zhang

et al.

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 4, 2025

Abstract Neuronal cell death is a causative process in traumatic brain injury (TBI)-induced structural and functional impairment of the central nervous system. However, upstream trigger TBI-induced neuronal loss underlying molecular pathways remain unclear. Zipper-interacting protein kinase (ZIPK) has been shown to be upregulated Alzheimer’s disease ischemic stroke play role cellular apoptosis, while its pathological significance TBI not reported. Herein, we discovered for first time that ZIPK expression was markedly elevated neurons after caused massive apoptosis peri-contusional regions. Zipk haploinsufficiency antagonized reversed several typical neuropathological changes induced by TBI. Mechanistically, found affected viability modulating effector domain-containing DNA binding (DEDD) caspase-3 pathway. Specifically, could bind phosphorylate DEDD at S9 residue, thus enhancing stability DEDD, leading activation caspase-3-mediated apoptotic cascade neurons. The rescue downregulation effectively alleviated behavioral deficits preserving motor cognitive abilities vivo, supporting decisive dysregulation TBI-associated dysfunctions survival. Furthermore, pharmacological suppression activity specific inhibitor prior protected from injury-induced degeneration vitro vivo preventing upregulation activation. In conclusion, our data reveal essential contribution through DEDD/caspase-3 cascade, suggest potential targeting as an effective strategy treating TBI-related neuropathologies.

Language: Английский

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