Central nervous system-specific knockout of Brg1 causes growth retardation and neuronal degeneration

Deng, Li; Li, Guibo; Rao, Benqiang; Li, Huashun

doi:10.1016/j.brainres.2015.06.027

Cited by 17 publications

(10 citation statements)

References 44 publications

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“…12b). In neurons, BRG1 is a transcription factor which is critical for neuronal development, gliogenesis, and normal gene expression [refs], and for which loss has been associated with neurodegeneration and neuronal cell loss [31]. In addition, cases with evidence of DNA damage in glial cells showed translocation of intranuclear tau to the cytoplasm (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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Section: Resultsmentioning

confidence: 99%

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

Schwab

Hazrati

2019

acta neuropathol commun

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“…HIF-1α is neuroprotective after mild hypoxia, but neurotoxic after more severe hypoxia (Fan et al, 2009). Smarca4 (human gene BRG1 ) is involved in the developmental switch from neurogenesis to gliogenesis (Deng et al, 2015), and could mediate reactive astrocytosis.…”

Section: Discussionmentioning

confidence: 99%

Altered gene expression profile in a mouse model of SCN8A encephalopathy

Sprissler

Wagnon

Bunton-Stasyshyn

et al. 2017

Experimental Neurology

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SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.

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“…Deng et al found that under oxidative stress, the number of damaged and dead neurons in BRG1 knockout (KO) mice increased significantly, which may be related to the regulation of NR2B-NR2A by BRG1 [ 44 ]. Overexpression of BRG1 increases the activity of neurons, weakens apoptosis, and reduces the production of ROS, thus producing a protective effect on oxygen-glucose deprivation/reoxygenation- (OGD/R-) induced injury [ 45 ].…”

Section: Brg1 In Oxidative Stress Signalingmentioning

confidence: 99%

The Role of BRG1 in Antioxidant and Redox Signaling

You

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Redox homeostasis is regulated by critical molecules that modulate antioxidant and redox signaling (ARS) within the cell. Imbalances among these molecules can lead to oxidative stress and damage to cell functions, causing a variety of diseases. Brahma-related gene 1 (BRG1), also known as SMARCA4, is the central ATPase catalytic subunit of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex, which plays a core role in DNA replication, repair, recombination, and transcriptional regulation. Numerous recent studies show that BRG1 is involved in the regulation of various cellular processes associated with ARS. BRG1, as a major factor in chromatin remodeling, is essential for the repair of oxidative stress-induced DNA damage and the activation of antioxidant genes under oxidative stress. Consequently, a comprehensive understanding of the roles of BRG1 in redox homeostasis is crucial to understand the normal functioning as well as pathological mechanisms. In this review, we summarized and discussed the role of BRG1 in the regulation of ARS.

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Central nervous system-specific knockout of Brg1 causes growth retardation and neuronal degeneration

Cited by 17 publications

References 44 publications

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

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

Altered gene expression profile in a mouse model of SCN8A encephalopathy

The Role of BRG1 in Antioxidant and Redox Signaling

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