PRMT7 can prevent neurovascular uncoupling, blood-brain barrier permeability, and mitochondrial dysfunction in repetitive and mild traumatic brain injury

• Published in: Experimental neurology 2023-08, Vol.366, p.114445-114445, Article 114445
• Main Authors: Acosta, Christina H., Clemons, Garrett A., Citadin, Cristiane T., Carr, William C., Udo, Mariana Sayuri Berto, Tesic, Vesna, Sanicola, Henry W., Freelin, Anne H., Toms, Jamie B., Jordan, J. Dedrick, Guthikonda, Bharat, Rodgers, Krista M., Wu, Celeste Yin-Chieh, Lee, Reggie Hui-Chao, Lin, Hung Wen
• Format: Article
• Language: English
• Subjects: Bioenergetics; Blood-Brain Barrier; Brain Concussion; Brain Injuries, Traumatic; Cerebral blood flow; Gliosis; Humans; Leukocyte rolling; Mitochondrial dysfunction; Protein arginine methyltransferase; Protein-Arginine N-Methyltransferases; Respiration; Traumatic brain injury
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2023.114445

Mild traumatic brain injury (TBI) comprises the largest percentage of TBI-related injuries, with pathophysiological and functional deficits that persist in a subset of TBI patients. In our three-hit paradigm of repetitive and mild traumatic brain injury (rmTBI), we observed neurovascular uncoupling via decreased red blood cell velocity, microvessel diameter, and leukocyte rolling velocity 3 days post-rmTBI via intra-vital two-photon laser scanning microscopy. Furthermore, our data suggest increased blood-brain barrier (BBB) permeability (leakage), with corresponding decrease in junctional protein expression post-rmTBI. Mitochondrial oxygen consumption rates (measured via Seahorse XFe24) were also altered 3 days post-rmTBI, along with disrupted mitochondrial dynamics of fission and fusion. Overall, these pathophysiological findings correlated with decreased protein arginine methyltransferase 7 (PRMT7) protein levels and activity post-rmTBI. Here, we increased PRMT7 levels in vivo to assess the role of the neurovasculature and mitochondria post-rmTBI. In vivo overexpression of PRMT7 using a neuronal specific AAV vector led to restoration of neurovascular coupling, prevented BBB leakage, and promoted mitochondrial respiration, altogether to suggest a protective and functional role of PRMT7 in rmTBI. •Our 3-hit repetitive and mild traumatic brain injury (rmTBI) paradigm contributed to cerebral blood flow derangements, blood brain barrier permeability, decreased leukocyte velocities, gliosis, and mitochondrial dysfunction.•Endogenous protein arginine methyltransferase 7 (PRMT7) protein levels and activity decrease in repetitive and mild traumatic brain injury (rmTBI).•In vivo overexpression of PRMT7 via AAV/PHP.eB-hSYN1-GFP.mPRMT7-WPRE vector attenuated the rmTBI pathologies.•First to identify a functional role of PRMT7 in rmTBI.