Senescence-associated-β-galactosidase staining following traumatic brain injury in the mouse cerebrum

Tominaga, Tadasuke; Shimada, Ryo; Okada, Yoshikazu; Kawamata, Takakazu; Kibayashi, Kazuhiko

doi:10.1371/journal.pone.0213673

Cited by 57 publications

(51 citation statements)

References 37 publications

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“…Because TBI increases senescence-associated β-gal activity at pH 6.0 (Tominaga et al, 2019), we performed X-gal staining at pH 7.4 in the TBI-induced brain of the wild-type mice. No X-gal staining was observed in the TBI-induced brain of the wild-type mouse, indicating no senescence-associated β-gal activity in this assay system.…”

Section: Resultsmentioning

confidence: 99%

FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of FAM19A5-LacZ Knock-in Mice

Shahapal

Cho²,

Yong

et al. 2019

Front. Neurosci.

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FAM19A5 is a secretory protein that is predominantly expressed in the brain. Although the FAM19A5 gene has been found to be associated with neurological and/or psychiatric diseases, only limited information is available on its function in the brain. Using FAM19A5-LacZ knock-in mice, we determined the expression pattern of FAM19A5 in developing and adult brains and identified cell types that express FAM19A5 in naïve and traumatic brain injury (TBI)–induced brains. According to X-gal staining results, FAM19A5 is expressed in the ventricular zone and ganglionic eminence at a very early stage of brain development, suggesting its functions are related to the generation of neural stem cells and oligodendrocyte precursor cells (OPCs). In the later stages of developing embryos and in adult mice, FAM19A5 expression expanded broadly to particular regions of the brain, including layers 2/3 and 5 of the cortex, cornu amonis (CA) region of the hippocampus, and the corpus callosum. X-gal staining combined with immunostaining for a variety of cell-type markers revealed that FAM19A5 is expressed in many different cell types, including neurons, OPCs, astrocytes, and microglia; however, only some populations of these cell types produce FAM19A5. In a subpopulation of neuronal cells, TBI led to increased X-gal staining that extended to the nucleus, marked by slightly condensed content and increased heterochromatin formation along the nuclear border. Similarly, nuclear extension of X-gal staining occurred in a subpopulation of OPCs in the corpus callosum of the TBI-induced brain. Together, these results suggest that FAM19A5 plays a role in nervous system development from an early stage and increases its expression in response to pathological conditions in subsets of neurons and OPCs of the adult brain.

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Section: Resultsmentioning

confidence: 99%

FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of FAM19A5-LacZ Knock-in Mice

Shahapal

Cho²,

Yong

et al. 2019

Front. Neurosci.

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“…The role of senescent cells in cognitive decline and p-tau pathology has been demonstrated in a transgenic mouse model of AD, in which eliminating senescent cells through senolytic intervention resulted in reduced tau phosphorylation, improved cognitive outcomes, and the prevention of the upregulation of senescence genes [14]. In the context of TBI, markers of senescence have been shown to elevate in microglia and astrocytes following a controlled cortical impact protocol [153]. Contrary to studies showing vascular dysfunction in mTBI [2, 157], we did not see evidence of cellular senescence in endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

“…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]. More recently, 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].…”

Section: Introductionmentioning

confidence: 89%

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

Schwab

Hazrati

2019

acta neuropathol commun

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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.

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“…Pharmacological inhibitors of cell cycle flavopiridol, roscovitine and olomoucine were observed to suppress DNA damaging agent, etoposide-induced apoptosis in rat primary cortical neurons [ 114 ]. Wide-spread cell cycle stimulation and associated neuronal death was observed in rat brains subjected to traumatic injury [ 185 , 186 ]. Flavopiridol treatment interestingly, could attenuate cyclin D1 expression and consequently cell cycle activation in neurons and glia in brains of these animals.…”

Section: Cell Cycle Machinery Targeting Compounds As Neuroprotective mentioning

confidence: 99%

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

Joseph¹,

Mangani²,

Gupta³

et al. 2020

Aging and disease

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Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.

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Senescence-associated-β-galactosidase staining following traumatic brain injury in the mouse cerebrum

Cited by 57 publications

References 37 publications

FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of FAM19A5-LacZ Knock-in Mice

FAM19A5 Expression During Embryogenesis and in the Adult Traumatic Brain of FAM19A5-LacZ Knock-in Mice

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

Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development

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