The Role of DNA Damage-induced Cellular Senescence in the Pathophysiology of mTBI

The pathophysiological mechanism whereby mTBI leads to chronic symptoms and neuropathology is unknown, although it is known that cellular senescence underlies several neurological disorders. I hypothesize that mTBI causes DNA damage-induced cellular senescence, leading to the acute and chronic neurological dysfunction reported in individuals who have suffered from mTBI. Using a cohort of 38 donated brains with mTBI history, I have found extensive DNA damage with immunohistochemistry (γH2AX, a marker of double-stranded DNA breaks) not seen in control brains. Furthermore, gene expression analysis using NanoString revealed activation of DNA damage response pathways, insufficient expression of DNA repair proteins, and upregulation of pro-inflammatory and cellular senescence pathways. This study suggests that DNA damage-induced cellular senescence may be the underlying pathophysiological mechanism of acute and chronic brain dysfunction after mTBI, and represents potential therapeutic targets for treatment of mTBI-induced brain dysfunction.M.Sc.2020-10-31 00:00:0