Emerging roles of p53 in glial cell function in health and disease

Jebelli, Joseph; Hooper, Claudie; Garden, Gwenn A.; Pocock, Jennifer M.

doi:10.1002/glia.22268

Cited by 23 publications

(24 citation statements)

References 133 publications

(130 reference statements)

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“…The relationship between p53 and glial cells in a pathological context has been poorly studied until recently, and the evidence emerging suggests a contribution of astrocytic p53 to some neurodegenerative diseases (for review see (Jebelli et al, 2012). Our results support the idea that p53 is important in the response to Fxn depletion, not only in neurons (Palomo et al, 2011) but also in glial cells.…”

Section: Accepted Manuscriptsupporting

confidence: 85%

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Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Loría

Díaz‐Nido

2015

Neurobiology of Disease

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Friedreich's ataxia (FA) is a recessive, predominantly neurodegenerative disorder caused in most cases by mutations in the first intron of the frataxin (FXN) gene. This mutation drives the expansion of a homozygous GAA repeat that results in decreased levels of FXN transcription and frataxin protein. Frataxin (Fxn) is a ubiquitous mitochondrial protein involved in iron-sulfur cluster biogenesis, and a decrease in the levels of this protein is responsible for the symptoms observed in the disease. Although the pathological manifestations of FA are mainly observed in neurons of both the central and peripheral nervous system, it is not clear if changes in non-neuronal cells may also contribute to the pathogenesis of FA, as recently suggested for other neurodegenerative disorders. Therefore, the aims of this study were to generate and characterize a cell model of Fxn deficiency in human astrocytes (HAs) and to evaluate the possible involvement of non-cell autonomous processes in FA. To knockdown frataxin in vitro, we transduced HAs with a specific shRNA lentivirus (shRNA37), which produced a decrease in both frataxin mRNA and protein expression, along with mitochondrial superoxide production, and signs of p53-mediated cell cycle arrest and apoptotic cell death. To test for non-cell autonomous interactions we cultured wild-type mouse neurons in the presence of frataxin-deficient astrocyte conditioned medium, which provoked a delay in the maturation of these neurons, a decrease in neurite length and enhanced cell death. Our findings confirm a detrimental effect of frataxin silencing, not only for astrocytes, but also for neuron-glia interactions, underlining the need to take into account the role of non-cell autonomous processes in FA.

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Section: Accepted Manuscriptsupporting

confidence: 85%

“…The transcription factor p53 plays a key role in regulating events like DNA repair and the cell cycle (Jebelli et al, 2012). Moreover, p53 is involved in the induction of apoptosis, particularly in a neuronal model of Fxn silencing (Palomo et al, 2011).…”

Section: Signs Of Possible Cell Cycle Arrest and Apoptosis In Human Amentioning

confidence: 99%

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Loría

Díaz‐Nido

2015

Neurobiology of Disease

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“…Although the roles microglia play in the injured CNS are still under investigation, an emerging theme is that glia contribute to the pathogenesis of neurological diseases via a non cell-autonomous mechanism (8). Microglia behavior during inflammation can lead to: i) loss of normal function in other neuroglia that subsequently trigger downstream damage to vulnerable neurons; and ii) direct neuronal toxicity (9).…”

Section: Introductionmentioning

confidence: 99%

“…The transcription factor p53 is best known as a regulator of cell-cycle control and apoptosis in response to discrete cellular insults (8). Under basal conditions, p53 is ubiquitnated and rapidly degraded.…”

Section: Introductionmentioning

confidence: 99%

The p53 Transcription Factor Modulates Microglia Behavior through MicroRNA-Dependent Regulation of c-Maf

Hopkins

Nesser

et al. 2014

The Journal of Immunology

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Neuroinflammation occurs in acute and chronic CNS injury, including stroke, traumatic brain injury and neurodegenerative diseases. Microglia are specialized resident myeloid cells that mediate CNS innate immune responses. Disease relevant stimuli such as reactive oxygen species (ROS) can influence microglia activation. Previously we observed that p53, a ROS responsive transcription factor, modulates microglia behaviors in vitro and in vivo, promoting pro-inflammatory functions and suppressing down-regulation of the inflammatory response and tissue repair. Here we describe a novel mechanism by which p53 modulates the functional differentiation of microglia both in vitro and in vivo. Adult microglia from p53deficient mice have increased expression of the anti-inflammatory transcription factor c-Maf. To determine how p53 negatively regulates c-Maf, we examined the impact of p53 on known c-Maf regulators. MiR-155 is a microRNA (miRNA) that targets c-Maf. We observed that cytokine induced expression of miR-155 was suppressed in p53 deficient microglia. Furthermore, Twist2, a transcriptional activator of c-Maf, is increased in p53 deficient microglia. We identified recognition sites in the 3′ untranslated region of Twist2 mRNA that are predicted to interact with two p53 dependent miRNAs: miR-34a and miR-145. Here we demonstrate that miR-34a and -145 are regulated by p53 and negatively regulate Twist2 and c-Maf expression in microglia and the RAW macrophage cell line. Taken together, these findings support the hypothesis that p53 activation induced by local ROS or accumulated DNA damage, influences microglia functions and that one specific molecular target of p53 in microglia is c-Maf.

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“…Thus, although well described to play a multi-faceted role in regulating the outcome of cell stress in a variety of cell types and tissues, this report highlights the importance of p53 in regulating astroglial cell fate following stress. The precise role of p53 in astrocytes and the astroglial response to injury remains unknown [50]. In this study, hypoxia had no additive effect on endothelial gene expression compared to serum deprivation alone suggesting that the key driver for astrocyte cellular plasticity is through a withdrawal of growth factors or cell surface energy detection that ultimately signal through p53.…”

Section: Discussionmentioning

confidence: 70%

Astrocytes Can Adopt Endothelial Cell Fates in a p53-Dependent Manner

et al. 2016

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Astrocytes respond to a variety of CNS injuries by cellular enlargement, process outgrowth, and upregulation of extracellular matrix proteins that function to prevent expansion of the injured region. This astrocytic response, though critical to the acute injury response, results in the formation of a glial scar that inhibits neural repair. Scar forming cells (fibroblasts) in the heart can undergo mesenchymal-endothelial transition into endothelial cell fates following cardiac injury in a process dependent on p53 that can be modulated to augment cardiac repair. Here, we sought to determine whether astrocytes, as the primary scar-forming cell of the CNS, are able to undergo a similar cellular phenotypic transition and adopt endothelial cell fates. Serum deprivation of differentiated astrocytes resulted in a change in cellular morphology and upregulation of endothelial cell marker genes. In a tube formation assay, serum deprived astrocytes showed a substantial increase in vessel-like morphology that was comparable to human umbilical vein endothelial cells and dependent on p53. RNA-sequencing of serum-deprived astrocytes demonstrated an expression profile that mimicked an endothelial rather than astrocyte transcriptome and identified p53 and angiogenic pathways as specifically up-regulated. Inhibition of p53 with genetic or pharmacologic strategies inhibited astrocyte-endothelial transition. Astrocyte-endothelial cell transition could also be modulated by miR-194, a microRNA downstream of p53 that affects expression of genes regulating angiogenesis. Together, these studies demonstrate that differentiated astrocytes retain a stimulus-dependent mechanism for cellular transition into an endothelial phenotype that may modulate formation of the glial scar and promote injury-induced angiogenesis.

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Emerging roles of p53 in glial cell function in health and disease

Cited by 23 publications

References 133 publications

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

Frataxin knockdown in human astrocytes triggers cell death and the release of factors that cause neuronal toxicity

The p53 Transcription Factor Modulates Microglia Behavior through MicroRNA-Dependent Regulation of c-Maf

Astrocytes Can Adopt Endothelial Cell Fates in a p53-Dependent Manner

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