The Phosphorylated Form of the Histone H2AX (γH2AX) in the Brain from Embryonic Life to Old Age

Merighi, Adalberto; Gionchiglia, Nadia; Granato, Alberto; Lossi, Laura

doi:10.3390/molecules26237198

Cited by 30 publications

(27 citation statements)

References 218 publications

(273 reference statements)

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“…Therefore, it is important to emphasize that despite different genetic backgrounds, similar effects on genomic DNA have been described in the different ALS models. Histone 2ax has also been shown to play a key role, in both, the registration of increased ROS levels and in the initiation of various DNA damage response components (Kuo and Yang, 2008 ; Podhorecka et al, 2010 ; Barral et al, 2014 ; Merighi et al, 2021 ). Interestingly, H2ax-knock out mice exhibit dysfunctional motor characteristics, such as an impaired overall motor activity as well as impaired motor balance, among others (Weyemi et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

ROS scavengers decrease γH2ax spots in motor neuronal nuclei of ALS model mice in vitro

Junghans

John

Cihankaya

et al. 2022

Front. Cell. Neurosci.

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Background: Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by the loss of motor neurons in cerebral cortex, brainstem and spinal cord. Numerous studies have demonstrated signs of oxidative stress in postmortem neuronal tissue, cerebrospinal fluid, plasma and urine of ALS patients, without focusing on the specific processes within motor neurons. Thus, we aimed to investigate the relevance of reactive oxygen species (ROS) detoxification mechanisms and its consequences on the formation of toxic/lethal DNA double strand breaks (DSBs) in the ALS model of the Wobbler mouse.Methods: Live cell imaging in dissociated motor neuronal cultures was used to investigate the production of ROS using Dihydroethidium (DHE). The expression levels of ROS detoxifying molecules were investigated by qPCR as well as Western blots. Furthermore, the expression levels of DNA damage response proteins p53bp1 and H2ax were investigated using qPCR and immunofluorescence staining. Proof-of-principle experiments using ROS scavengers were performed in vitro to decipher the influence of ROS on the formation of DNA double strand breaks quantifying the γH2ax spots formation.Results: Here, we verified an elevated ROS-level in spinal motor neurons of symptomatic Wobbler mice in vitro. As a result, an increased number of DNA damage response proteins p53bp1 and γH2ax in dissociated motor neurons of the spinal cord of Wobbler mice was observed. Furthermore, we found a significantly altered expression of several antioxidant molecules in the spinal cord of Wobbler mice, suggesting a deficit in ROS detoxification mechanisms. This hypothesis could be verified by using ROS scavenger molecules in vitro to reduce the number of γH2ax foci in dissociated motor neurons and thus counteract the harmful effects of ROS.Conclusion: Our data indicate that maintenance of redox homeostasis may play a key role in the therapy of the neurodegenerative disease ALS. Our results underline a necessity for multimodal treatment approaches to prolong the average lifespan of motor neurons and thus slow down the progression of the disease, since a focused intervention in one pathomechanism seems to be insufficient in ALS therapy.

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Section: Discussionmentioning

confidence: 99%

ROS scavengers decrease γH2ax spots in motor neuronal nuclei of ALS model mice in vitro

Junghans

John

Cihankaya

et al. 2022

Front. Cell. Neurosci.

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“…While in wt , the number of γH2AX positive cells decline as expected after P14, in Cstb –/– cerebellum, the number stays high. Given that γH2AX is a pleiotropic molecule with an array of yet not fully understood functions in the brain, including response to oxidative damage and apoptotic signaling ( Merighi et al, 2021 ), the significance of its continued expression beyond P14 in Cstb –/– cerebellum should be explored in further studies. Interestingly, apoptotic cell death is one of the major pathological signs in Cstb –/– cerebellum ( Pennacchio et al, 1998 ) where oxidative damage has even been described, although not on DNA level ( Lehtinen et al, 2009 ).…”

Section: Discussionmentioning

confidence: 99%

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

Daura

Tegelberg²,

Hakala³

et al. 2022

Front. Mol. Neurosci.

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Cystatin B (CSTB) is a cysteine cathepsin inhibitor whose biallelic loss-of-function mutations in human result in defects in brain development and in neurodegeneration. The physiological function of CSTB is largely unknown, and the mechanisms underlying the human brain diseases remain poorly understood. We previously showed that CSTB modulates the proteolysis of the N-terminal tail of histone H3 (H3cs1) during in vitro neurogenesis. Here we investigated the significance of this mechanism in postnatal mouse brain. Spatiotemporal analysis of H3cs1 intensity showed that while H3cs1 in wild-type (wt) mice was found at varying levels during the first postnatal month, it was virtually absent in adult brain. We further showed that the high level of H3cs1 coincides with chromatin association of de novo synthesized cathepsin L suggesting a role for nuclear cathepsin L in brain development and maturation. On the contrary, the brains of Cstb–/– mice showed sustained H3cs1 proteolysis to adulthood with increased chromatin-associated cathepsin L activity, implying that CSTB regulates chromatin-associated cathepsin L activity in the postnatal mouse brain. As H3 tail proteolysis has been linked to cellular senescence in vitro, we explored the presence of several cellular senescence markers in the maturing Cstb–/– cerebellum, where we see increased levels of H3cs1. While several markers showed alterations in Cstb–/– mice, the results remained inconclusive regarding the association of deficient CSTB function with H3cs1-induced senescence. Together, we identify a molecular role for CSTB in brain with implications for brain development and disease.

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“…γH2AX is observed during embryonic and adult neurogenesis and appears to be involved in neuronal proliferation and differentiation. 145 , 146 The exact role of γH2AX during neurogenesis needs to be examined.…”

Section: Histone Modification In Neurogenesismentioning

confidence: 99%

The role of histone modifications: from neurodevelopment to neurodiseases

Park

Lee

Kim

et al. 2022

Sig Transduct Target Ther

126

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Epigenetic regulatory mechanisms, including DNA methylation, histone modification, chromatin remodeling, and microRNA expression, play critical roles in cell differentiation and organ development through spatial and temporal gene regulation. Neurogenesis is a sophisticated and complex process by which neural stem cells differentiate into specialized brain cell types at specific times and regions of the brain. A growing body of evidence suggests that epigenetic mechanisms, such as histone modifications, allow the fine-tuning and coordination of spatiotemporal gene expressions during neurogenesis. Aberrant histone modifications contribute to the development of neurodegenerative and neuropsychiatric diseases. Herein, recent progress in understanding histone modifications in regulating embryonic and adult neurogenesis is comprehensively reviewed. The histone modifications implicated in neurodegenerative and neuropsychiatric diseases are also covered, and future directions in this area are provided.

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The Phosphorylated Form of the Histone H2AX (γH2AX) in the Brain from Embryonic Life to Old Age

Cited by 30 publications

References 218 publications

ROS scavengers decrease γH2ax spots in motor neuronal nuclei of ALS model mice in vitro

ROS scavengers decrease γH2ax spots in motor neuronal nuclei of ALS model mice in vitro

Cystatin B deficiency results in sustained histone H3 tail cleavage in postnatal mouse brain mediated by increased chromatin-associated cathepsin L activity

The role of histone modifications: from neurodevelopment to neurodiseases

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