DNA repair deficiency and senescence in concussed professional athletes involved in contact sports

Abstract

Mild traumatic brain injury (mTBI) leads to diverse symptoms including mood disorders, cognitive decline, and behavioral changes. In some individuals, these symptoms become chronic and persist in the long-term and can confer an increased risk of neurodegenerative disease and dementia diagnosis later in life. Despite the severity of its consequences, the pathophysiological mechanism of mTBI remains unknown. In this post-mortem case series, we assessed DNA damage-induced cellular senescence pathways in 38 professional athletes with a history of repeated mTBI and ten controls with no mTBI history. We assessed clinical presentation, neuropathological changes, load of DNA damage, morphological markers of cellular senescence, and expression of genes involved in DNA damage signaling, DNA repair, and cellular senescence including the senescence-associated secretory phenotype (SASP). Twenty-eight brains with past history of repeated mTBI history had DNA damage within ependymal cells, astrocytes, and oligodendrocytes. DNA damage burden was increased in brains with proteinopathy compared to those without. Cases also showed hallmark features of cellular senescence in glial cells including astrocytic swelling, beading of glial cell processes, loss of H3K27Me3 (trimethylation at lysine 27 of histone H3) and lamin B1 expression, and increased expression of cellular senescence and SASP pathways. Neurons showed a spectrum of changes including loss of emerin nuclear membrane expression, loss of Brahma-related gene-1 (BRG1 or SMARCA4) expression, loss of myelin basic protein (MBP) axonal expression, and translocation of intranuclear tau to the cytoplasm. Expression of DNA repair proteins was decreased in mTBI brains. mTBI brains showed substantial evidence of DNA damage and cellular senescence. Decreased expression of DNA repair genes suggests inefficient DNA repair pathways in this cohort, conferring susceptibly to cellular senescence and subsequent brain dysfunction after mTBI. We therefore suggest that brains of contact-sports athletes are characterized by deficient DNA repair and DNA damage-induced cellular senescence and propose that this may affect neurons and be the driver of brain dysfunction in mTBI, predisposing the progression to neurodegenerative diseases. This study provides novel targets for diagnostic and prognostic biomarkers, and represents viable targets for future treatments.

Cellular senescence in the aging retina and developments of senotherapies for age-related macular degeneration

“…Circumstantial evidence from murine models of diabetes-induced retinopathy and defects in lipoprotein receptor indicates inflammatory secretion of IL-1α, IL-1β, IL-6, IL-12, TNF-α, MCP-1, CCL25, CXCL1, CXCL12a, and I-309 by abnormal photoreceptors [ 125 , 126 ]. Of note, such proinflammatory mediators derived from altered photoreceptors are all recognized or reported SASP components in other cell types or tissues [ 127 – 130 ]. The involvement of SASP in AMD has clinical manifestation too, as a number of inflammatory cytokines have been uncovered to be elevated either systemically in the sera or locally in the aqueous humor of patients with AMD, particularly IL-6, IL-8, IL-12, MCP-1, TNF-α, IL-1α, IL-1β, and IL-17 [ 82 , 123 , 131 ].…”

Early onset senescence and cognitive impairment in a murine model of repeated mTBI

“…This can lead to widespread DNA damage [ 28 ]. Indeed, accumulation of DNA damage has been reported in various models of mTBI [ 3 , 123 , 151 ] and our lab has previously shown evidence of double-strand breaks (DSBs) in human brains with mTBI history [ 131 , 132 ]. Although cells throughout the body regularly encounter DNA damage from endogenous sources, such as metabolic reactive oxygen species (ROS), the cell’s DNA damage response (DDR) can become overwhelmed when facing pathological levels of damage.…”

Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia

“…The main focus of pharmacological research over the past 50 years has been the identification of cognitive enhancers; however, no US Food and Drug Administration (FDA)-approved drugs for AD have been reported for the past two decades [7]. Behavioral disorders (BDs) (psychotic, depressive, anxiety, sleep disorders, and inappropriate sexual behaviors) are common (10- There is not a prototypical pattern of BDs in different dementia types; however, BDs tend to be more prevalent in FTD, in cases where the compromise of frontotemporal regions is more relevant [18][19][20], and in cases with mild traumatic brain injury (TBI) [21] where DNA damage-induced cellular senescence pathways have been identified [22]. Apathy, depression, dysphoria, agitation, aggression, hallucinations, and delusions are frequent distressing symptoms in dementia [14].…”