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Published on: January 3, 2025
Oxidative DNA Damage Mediated by Intranuclear MMP Activity Is Associated with Neuronal Apoptosis in Ischemic Stroke
Shihoko Kimura-Ohba1, Yi Yang1
1Department of Neurology, School of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
Abstract:
Evidence of the pathological roles of matrix metalloproteinases (MMPs) in various neurological disorders has made them attractive therapeutic targets. MMPs disrupt the blood-brain barrier and cause neuronal death and neuroinflammation in acute cerebral ischemia and are critical for angiogenesis during recovery. However, some challenges have to be overcome before MMPs can be further validated as drug targets in stroke injury. Identifying in vivo substrates of MMPs should greatly improve our understanding of the mechanisms of ischemic injury and is critical for providing more precise drug targets. Recent works have uncovered nontraditional roles for MMPs in the cytosol and nucleus. These have shed light on intracellular targets and biological actions of MMPs, adding additional layers of complexity for therapeutic MMP inhibition. In this review, we discussed the recent advances made in understanding nuclear location of MMPs, their regulation of intranuclear sorting, and their intranuclear proteolytic activity and substrates. In particular, we highlighted the roles of intranuclear MMPs in oxidative DNA damage, neuronal apoptosis, and neuroinflammation at an early stage of stroke insult. These novel data point to new putative MMP-mediated intranuclear actions in stroke-induced pathological processes and may lead to novel approaches to treatment of stroke and other neurological diseases.
Insights
Matrix metalloproteinases (MMPs) play pathological roles in neurological disorders. This review highlights novel nuclear functions of MMPs in stroke, suggesting new therapeutic targets for stroke and other brain diseases.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Matrix metalloproteinases (MMPs) are implicated in neurological disorders, affecting the blood-brain barrier, neuronal death, and neuroinflammation.
- MMPs are crucial for angiogenesis during recovery from acute cerebral ischemia.
- Challenges remain in validating MMPs as drug targets for stroke due to complexities in their functions.
Purpose of the Study:
- To review recent advances in understanding the nuclear localization, regulation, and activity of MMPs.
- To highlight the roles of intranuclear MMPs in early-stage stroke pathology.
- To identify novel MMP-mediated intranuclear actions and potential therapeutic strategies.
Main Methods:
- Literature review of recent research on MMPs in neurological disorders.
- Focus on studies investigating intracellular MMP localization and function.
- Analysis of MMP substrates and their roles in cellular processes.
Main Results:
- MMPs exhibit nontraditional roles in the cytosol and nucleus, revealing intracellular targets.
- Intranuclear MMPs are involved in oxidative DNA damage, neuronal apoptosis, and neuroinflammation.
- Novel MMP-mediated intranuclear actions contribute to stroke-induced pathological processes.
Conclusions:
- Understanding nuclear MMP functions provides new insights into stroke mechanisms.
- Intranuclear MMPs represent potential targets for novel therapeutic interventions.
- Further research into MMPs may lead to improved treatments for stroke and other neurological diseases.
