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

Karl Grenier,Nicole Schwab,Lili-Naz Hazrati

doi:10.1186/s40478-019-0822-3

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.

Highlights

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, affecting an estimated 10 million individuals each year [62]
Involvement in contact sports and a history of multiple concussions has been shown to cause long-term effects on brain health [27, 88, 95] and many studies have credited neurodegenerative diseases as the chief driver of these long-term symptoms and pathological changes [3, 102, 144, 145]. mild TBI (mTBI) has been linked to several different neurodegenerative diseases, and in particular chronic traumatic encephalopathy (CTE) has been proposed as the pathological signature of concussion and the driver of symptoms [107]
A major gap in knowledge in our understanding of mTBIassociated brain dysfunction is the discordance between the pathology load and severity of symptoms, often in younger individuals: cases with a history of head trauma often have microscopic foci of proteinopathy, yet present with severe and diverse symptoms [134]

Summary

Introduction

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, affecting an estimated 10 million individuals each year [62]. Schwab et al Acta Neuropathologica Communications (2019) 7:182 addition to these symptoms, a history of mTBI has been associated with an increased risk of being diagnosed with dementia and/or a neurodegenerative disease [36, 44, 90], including Alzheimer’s disease (AD) [112], amyotrophic lateral sclerosis (ALS) [17], Parkinson’s disease (PD) [71], frontotemporal dementia (FTD) [129], and, more recently, chronic traumatic encephalopathy (CTE) [99, 101]. The pathophysiological mechanism driving brain dysfunction after mTBI, including lingering long-term symptoms and the propensity towards neurodegenerative disease, remains unknown. The accumulation of senescent cells in the brain is thought to drive ageing and age-related diseases [155], cognitive decline [6], and neurodegenerative pathology [81]. Markers of senescence were shown to be elevated in a mouse model of mTBI [153] and, in our previous work, we have shown evidence of DNA damage in human cases with a history of acute and chronic mTBI [135]

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Conclusion