A Role for Protein Arginine Methyltransferase 7 in Repetitive and Mild Traumatic Brain Injury

Authors

Christina H Acosta
Garrett A Clemons
Cristiane T Citadin
William C Carr
Mariana Sayuri Berto Udo
Vesna Tesic
Henry W Sanicola
Anne H Freelin
Jamie B Toms
J Dedrick Jordan
Bharat Guthikonda
Celeste Yin-Chieh Wu
Reggie Hui-Chao Lee
Hung Wen Lin

Publication Date

6-1-2023

Journal

Neurochemistry International

Abstract

Mild traumatic brain injury affects the largest proportion of individuals in the United States and world-wide. Pre-clinical studies of repetitive and mild traumatic brain injury (rmTBI) have been limited in their ability to recapitulate human pathology (i.e. diffuse rotational injury). We used the closed-head impact model of engineered rotation acceleration (CHIMERA) to simulate rotational injury observed in patients and to study the pathological outcomes post-rmTBI using C57BL/6J mice. Enhanced cytokine production was observed in both the cortex and hippocampus to suggest neuroinflammation. Furthermore, microglia were assessed via enhanced iba1 protein levels and morphological changes using immunofluorescence. In addition, LC/MS analyses revealed excess glutamate production, as well as diffuse axonal injury via Bielschowsky's silver stain kit. Moreover, the heterogeneous nature of rmTBI has made it challenging to identify drug therapies that address rmTBI, therefore we sought to identify novel targets in the concurrent rmTBI pathology. The pathophysiological findings correlated with a time-dependent decrease in protein arginine methyltransferase 7 (PRMT7) protein expression and activity post-rmTBI along with dysregulation of PRMT upstream mediators s-adenosylmethionine and methionine adenosyltransferase 2 (MAT2) in vivo. In addition, inhibition of the upstream mediator MAT2A using the HT22 hippocampal neuronal cell line suggest a mechanistic role for PRMT7 via MAT2A in vitro. Collectively, we have identified PRMT7 as a novel target in rmTBI pathology in vivo and a mechanistic link between PRMT7 and upstream mediator MAT2A in vitro.

Keywords

Animals, Humans, Mice, Brain Concussion, Brain Injuries, Traumatic, Cerebral Cortex, Disease Models, Animal, Hippocampus, Methionine Adenosyltransferase, Mice, Inbred C57BL, Protein-Arginine N-Methyltransferases

Comments

Supplementary Materials

Data Availability Statement

PMID: 37030326