Transcriptional and epigenetic regulation of ncx1 and ncx3 in the brain

Formisano, Luigi; Guida, Natascia; Mascolo, Luigi; Serani, Angelo; Laudati, Giusy; Pizzorusso, Vincenzo; Annunziato, Lucio

doi:10.1016/j.ceca.2020.102194

Cited by 18 publications

(7 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another aspect that should be considered is that it has also been reported that the pharmacological inhibition of other HDACs isoforms, including HDAC class I, might also exert a role in neuronal ferroptosis in stroke 16 . However, although we found that HDAC1, 2, 4 and 5 isoforms increased in primary cortical neurons after OGD/Rx 30 , 54 , here we also found that the silencing of these epigenetic factors did not affect TfR1 and GPX4 gene expression. These data reinforce the hypothesis that HDAC9 selectively promotes ferroptotic neuronal death by means of TfR1 and GPX4.…”

Section: Discussioncontrasting

confidence: 68%

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

Sanguigno,

Guida,

Anzilotti

et al. 2023

Int. J. Biol. Sci.

Self Cite

View full text Add to dashboard Cite

Background: The inhibition of histone deacetylase 9 (HDAC9) represents a promising druggable target for stroke intervention. Indeed, HDAC9 is overexpressed in neurons after brain ischemia where exerts a neurodetrimental role. However, mechanisms of HDAC9-dependent neuronal cell death are not yet well established. Methods: Brain ischemia was obtained in vitro by primary cortical neurons exposed to glucose deprivation plus reoxygenation (OGD/Rx) and in vivo by transient middle cerebral artery occlusion. Western blot and quantitative real-time polymerase chain reaction were used to evaluate transcript and protein levels. Chromatin immunoprecipitation was used to evaluate the binding of transcription factors to the promoter of target genes. Cell viability was measured by MTT and LDH assays. Ferroptosis was evaluated by iron overload and 4-hydroxynonenal (4-HNE) release. Results: Our results showed that HDAC9 binds to hypoxia-inducible factor 1 (HIF-1) and specificity protein 1 (Sp1), two transcription activators of transferrin 1 receptor (TfR1) and glutathione peroxidase 4 (GPX4) genes, respectively, in neuronal cells exposed to OGD/Rx. Consequently, HDAC9 induced: (1) an increase in protein level of HIF-1 by deacetylation and deubiquitination, thus promoting the transcription of the pro-ferroptotic TfR1 gene; and (2) a reduction in Sp1 protein levels by deacetylation and ubiquitination, thus resulting in a down-regulation of the anti-ferroptotic GPX4 gene. Supporting these results, the silencing of HDAC9 partially prevented either HIF-1 increase and Sp1 reduction after OGD/Rx. Interestingly, silencing of the neurodetrimental factors, HDAC9, HIF-1, or TfR1 or the overexpression of the prosurvival factors Sp1 or GPX4 significantly reduced a well-known marker of ferroptosis 4-HNE after OGD/Rx. More important, in vivo , intracerebroventricular injection of siHDAC9 reduced 4-HNE levels after stroke by preventing: (1) HIF-1 and TfR1 increase and thus the augmented intracellular iron overload; and (2) a reduction of Sp1 and its target gene GPX4. Conclusions: Collectively, results obtained suggest that HDAC9 mediates post-traslational modifications of HIF-1 and Sp1 that, in turn, increases TfR1 and decreases GPX4 expression, thus promoting neuronal ferroptosis in in vitro and in vivo models of stroke.

show abstract

Section: Discussioncontrasting

confidence: 68%

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

Sanguigno,

Guida,

Anzilotti

et al. 2023

Int. J. Biol. Sci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…As a human ortholog, solute carrier family 8 member A has been implicated in AD and pulmonary hypertension. An alternative splicing variant (AD-CBD2) of ncx-1 is highly expressed in neurons and encodes the acidic segment of calcium-binding site 2, which enables binding with calcium to attenuate inactivation NCX1 caused by high sodium levels [ 46 ]. Although ncx-1 function have not well studied yet in worms, our findings suggest its high expression associated with calcium homeostasis and required for alleviating neuronal damage.…”

Section: Resultsmentioning

confidence: 99%

Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer’s Disease

Zheng

Ruan

et al. 2022

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Calcium homeostasis plays a vital role in protecting against Alzheimer’s disease (AD). In this study, amyloid-β (Aβ)-induced C. elegans models of AD were used to elucidate the mechanisms underlying calcium homeostasis in AD. Calcium acetate increased the intracellular calcium content, exacerbated Aβ1–42 aggregation, which is closely associated with oxidative stress, aggravated neuronal degeneration and dysfunction, and shortened the lifespan of the C. elegans models. Ethylene glycol tetraacetic acid (EGTA) and nimodipine were used to decrease the intracellular calcium content. Both EGTA and nimodipine showed remarkable inhibitory effects on Aβ1–42 aggregations by increasing oxidative stress resistance. Moreover, both compounds significantly delayed the onset of Aβ-induced paralysis, rescued memory deficits, ameliorated behavioral dysfunction, decreased the vulnerability of two major (GABAergic and dopaminergic) neurons and synapses, and extended the lifespan of the C. elegans AD models. Furthermore, RNA sequencing of nimodipine-treated worms revealed numerous downstream differentially expressed genes related to calcium signaling. Nimodipine-induced inhibition of selective voltage-gated calcium channels was shown to activate other calcium channels of the plasma membrane (clhm-1) and endoplasmic reticulum (unc-68), in addition to sodium-calcium exchanger channels (ncx-1). These channels collaborated to activate downstream events to resist oxidative stress through glutathione S-transferase activity mediated by HPGD and skn-1, as verified by RNA interference. These results may be applied for the treatment of Alzheimer’s disease.

show abstract

“…More important, the DREAM-dependent inhibition of ncx3 expression ultimately leads to the reduction of the neuroprotective effect exerted by this antiporter against stroke damage [25,46] (Figure 3). In fact, the pharmacological inhibition or genetic knock-down of DREAM show beneficial effects in experimental stroke, including tMCAO [47] and four vessel occlusion [44] models. On the other hand, opposite results were obtained with DREAM overexpression in an excitotoxicity neuronal model.…”

Section: Dream and Strokementioning

confidence: 99%

Emerging Role of DREAM in Healthy Brain and Neurological Diseases

Molinaro

Sanguigno

Casamassa³

et al. 2023

IJMS

Self Cite

View full text Add to dashboard Cite

The downstream regulatory element antagonist modulator (DREAM) is a multifunctional Ca2+-sensitive protein exerting a dual mechanism of action to regulate several Ca2+-dependent processes. Upon sumoylation, DREAM enters in nucleus where it downregulates the expression of several genes provided with a consensus sequence named dream regulatory element (DRE). On the other hand, DREAM could also directly modulate the activity or the localization of several cytosolic and plasma membrane proteins. In this review, we summarize recent advances in the knowledge of DREAM dysregulation and DREAM-dependent epigenetic remodeling as a central mechanism in the progression of several diseases affecting central nervous system, including stroke, Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis, and neuropathic pain. Interestingly, DREAM seems to exert a common detrimental role in these diseases by inhibiting the transcription of several neuroprotective genes, including the sodium/calcium exchanger isoform 3 (NCX3), brain-derived neurotrophic factor (BDNF), pro-dynorphin, and c-fos. These findings lead to the concept that DREAM might represent a pharmacological target to ameliorate symptoms and reduce neurodegenerative processes in several pathological conditions affecting central nervous system.

show abstract

Transcriptional and epigenetic regulation of ncx1 and ncx3 in the brain

Cited by 18 publications

References 62 publications

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

Stroke by inducing HDAC9-dependent deacetylation of HIF-1 and Sp1, promotes TfR1 transcription and GPX4 reduction, thus determining ferroptotic neuronal death

Suppression of Selective Voltage-Gated Calcium Channels Alleviates Neuronal Degeneration and Dysfunction through Glutathione S-Transferase-Mediated Oxidative Stress Resistance in a Caenorhabditis elegans Model of Alzheimer’s Disease

Emerging Role of DREAM in Healthy Brain and Neurological Diseases

Contact Info

Product

Resources

About