scholarly journals Antiglycative Activity and RAGE Expression in Rett Syndrome

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 161 ◽  
Author(s):  
Valeria Cordone ◽  
Alessandra Pecorelli ◽  
Mascia Benedusi ◽  
Silvano Santini ◽  
Stefano Falone ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurological Diseases ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
Cellular Stress Response ◽  
Defense Systems ◽  
Inflammatory Status ◽  
Glycation End Products ◽  
Rage Expression

Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults.

scholarly journals Cytokine Dysregulation inMECP2- andCDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, andω-3 PUFAs

2015 ◽  
Vol 2015 ◽  
pp. 1-18 ◽  
Author(s):  
Silvia Leoncini ◽  
Claudio De Felice ◽  
Cinzia Signorini ◽  
Gloria Zollo ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Redox Homeostasis ◽  
Clinical Severity ◽  
Cyclin Dependent Kinase ◽  
Omega 3 ◽  
Inflammatory Status ◽  
Cytokine Levels ◽  
Before And After ◽  
Cytokine Dysregulation

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated inMECP2- (MECP2-RTT) (n=16) andCDKL5-Rett syndrome (CDKL5-RTT) (n=8), before and afterω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. InMECP2-RTT, a Th2-shifted balance was evidenced, whereas inCDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. InMECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced inCDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.

scholarly journals Deficient Purposeful Use of Forepaws in Female Mice Modelling Rett Syndrome

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Bianca De Filippis ◽  
Mattia Musto ◽  
Luisa Altabella ◽  
Emilia Romano ◽  
Rossella Canese ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Motor Coordination ◽  
Neurodevelopmental Disorder ◽  
Fine Motor ◽  
Resonance Spectroscopy ◽  
Fine Motor Skill ◽  
Female Mice ◽  
Fine Grain ◽  
Motor Abnormalities

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioural and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases. Motor abnormalities represent a significant part of the spectrum of RTT symptoms. In the present study we investigated motor coordination and fine motor skill domains in MeCP2-308 female mice, a validated RTT model. This was complemented by thein vivomagnetic resonance spectroscopy (MRS) analysis of metabolic profile in behaviourally relevant brain areas. MeCP2-308 heterozygous female mice (Het, 10-12 months of age) were impaired in tasks validated for the assessment of purposeful and coordinated forepaw use (Morag testandCapellini handling task). A fine-grain analysis of spontaneous behaviour in the home-cage also revealed an abnormal handling pattern when interacting with the nesting material, reduced motivation to explore the environment, and increased time devoted to feeding in Het mice. The brain MRS evaluation highlighted decreased levels of bioenergetic metabolites in the striatal area in Het mice compared to controls. Present results confirm behavioural and brain alterations previously reported in MeCP2-308 males and identify novel endpoints on which the efficacy of innovative therapeutic strategies for RTT may be tested.

scholarly journals Persistent Unresolved Inflammation in the Mecp2-308 Female Mutated Mouse Model of Rett Syndrome

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Claudio De Felice ◽  
Bianca De Filippis ◽  
Laura Ricceri ◽  
Giovanni Laviola ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rett Syndrome ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Unknown Origin ◽  
Apolipoprotein A1 ◽  
Inflammatory Status ◽  
Truncating Mutation ◽  
Alpha 1 Antitrypsin ◽  
First Time

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2). Several Mecp2 mutant mouse lines have been developed recapitulating part of the clinical features. In particular, Mecp2-308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic Mecp2-308 female mice. Ten differentially expressed proteins were evidenced in the Mecp2-308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the Mecp2-308 mouse model.

scholarly journals Rescue of Methyl-CpG Binding Protein 2 Dysfunction-induced Defects in Newborn Neurons by Pentobarbital

2015 ◽  
Vol 12 (2) ◽  
pp. 477-490 ◽  
Author(s):  
Dongliang Ma ◽  
Su-In Yoon ◽  
Chih-Hao Yang ◽  
Guillaume Marcy ◽  
Na Zhao ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Hippocampal Neurons ◽  
Granule Cells ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Network Activity ◽  
Aminobutyric Acid ◽  
Structural Defects

Abstract Rett syndrome is a neurodevelopmental disorder that usually arises from mutations or deletions in methyl-CpG binding protein 2 (MeCP2), a transcriptional regulator that affects neuronal development and maturation without causing cell loss. Here, we show that silencing of MeCP2 decreased neurite arborization and synaptogenesis in cultured hippocampal neurons from rat fetal brains. These structural defects were associated with alterations in synaptic transmission and neural network activity. Similar retardation of dendritic growth was also observed in MeCP2-deficient newborn granule cells in the dentate gyrus of adult mouse brains in vivo, demonstrating direct and cell-autonomous effects on individual neurons. These defects, caused by MeCP2 deficiency, were reversed by treatment with the US Food and Drug Administration-approved drug, pentobarbital, in vitro and in vivo, possibly caused by modulation of γ-aminobutyric acid signaling. The results indicate that drugs modulating γ-aminobutyric acid signaling are potential therapeutics for Rett syndrome.

scholarly journals Subclinical Inflammatory Status in Rett Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Claudio De Felice ◽  
Roberto Guerranti ◽  
Cinzia Signorini ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Gene Mutation ◽  
Rett Syndrome ◽  
De Novo ◽  
Clinical Chemistry ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Protein Levels ◽  
Large Deletions ◽  
Inflammatory Status

Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused byde novoloss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., “pseudo-autistic”) RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four majorMECP2gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0 mm/h versus 8.0 mm/h,P<0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6spots) or negative (n=9spots), and to a lesser extent as proteins involved in the immune system (n=2spots), with some proteins having overlapping functions on metabolism (n=7spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by theMECP2gene mutation.

scholarly journals Brain-Derived Neurotrophic Factor Secreting Human Mesenchymal Stem Cells Improve Outcomes in Rett Syndrome Mouse Models

2021 ◽  
Vol 15 ◽  
Author(s):  
Hyo Jeong Kim ◽  
Delger Bayarsaikhan ◽  
Jaesuk Lee ◽  
Govigerel Bayarsaikhan ◽  
Bonghee Lee
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Rett Syndrome ◽  
Neurotrophic Factor ◽  
Neurodevelopmental Disorder ◽  
Neuronal Cell ◽  
Brain Derived Neurotrophic Factor ◽  
The Body ◽  
Human Umbilical Cord

Rett syndrome (RTT) is a severe X-linked dominant neurodevelopmental disorder caused by mutations in the methyl-CpG-binding protein 2 (MECP2) gene; MeCP2 regulates the expression of brain-derived neurotrophic factor (BDNF) and increasing BDNF levels ameliorates RTT symptoms. However, the clinical application of BDNF is limited, because of its short half-life and low penetrance across the blood-brain barrier. In this study, we generated BDNF-secreting mesenchymal stem cells (MSCs) from the human umbilical cord cells, using CRISPR-Cas9. We studied the effects of BDNF-MSCs in MECP2 knockout and MECP2-deficient mice. BDNF-MSCs upregulated the expression of BDNF, pAKT, and pERK1/2 and downregulated that of pp38, both in vitro and in vivo. In our in vivo experiments, BDNF-MSCs increased the body and brain weights in mice. BDNF-MSCs increased the neuronal cell numbers in the hippocampus, cortex, and striatum; in addition, they increased the number of synapses. BDNF-MSCs upregulated BDNF and the activity of BDNF downstream effectors, such as pAKT and pERK 1/2; this upregulation was persistent. In conclusion, BDNF-MSCs generated using CRISPR-Cas9 could be a therapeutic strategy for treating RTT.

scholarly journals JNK signaling provides a novel therapeutic target for Rett syndrome

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Clara Alice Musi ◽  
Anna Maria Castaldo ◽  
Anna Elisa Valsecchi ◽  
Sara Cimini ◽  
Noemi Morello ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Jnk Signaling ◽  
Functional Changes ◽  
Jnk Activation ◽  
Stress Pathway

Abstract Background Rett syndrome (RTT) is a monogenic X-linked neurodevelopmental disorder characterized by loss-of-function mutations in the MECP2 gene, which lead to structural and functional changes in synapse communication, and impairments of neural activity at the basis of cognitive deficits that progress from an early age. While the restoration of MECP2 in animal models has been shown to rescue some RTT symptoms, gene therapy intervention presents potential side effects, and with gene- and RNA-editing approaches still far from clinical application, strategies focusing on signaling pathways downstream of MeCP2 may provide alternatives for the development of more effective therapies in vivo. Here, we investigate the role of the c-Jun N-terminal kinase (JNK) stress pathway in the pathogenesis of RTT using different animal and cell models and evaluate JNK inhibition as a potential therapeutic approach. Results We discovered that the c-Jun N-terminal kinase (JNK) stress pathway is activated in Mecp2-knockout, Mecp2-heterozygous mice, and in human MECP2-mutated iPSC neurons. The specific JNK inhibitor, D-JNKI1, promotes recovery of body weight and locomotor impairments in two mouse models of RTT and rescues their dendritic spine alterations. Mecp2-knockout presents intermittent crises of apnea/hypopnea, one of the most invalidating RTT pathological symptoms, and D-JNKI1 powerfully reduces this breathing dysfunction. Importantly, we discovered that also neurons derived from hiPSC-MECP2 mut show JNK activation, high-phosphorylated c-Jun levels, and cell death, which is not observed in the isogenic control wt allele hiPSCs. Treatment with D-JNKI1 inhibits neuronal death induced by MECP2 mutation in hiPSCs mut neurons. Conclusions As a summary, we found altered JNK signaling in models of RTT and suggest that D-JNKI1 treatment prevents clinical symptoms, with coherent results at the cellular, molecular, and functional levels. This is the first proof of concept that JNK plays a key role in RTT and its specific inhibition offers a new and potential therapeutic tool to tackle RTT.

scholarly journals The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

2013 ◽  
Vol 304 (4) ◽  
pp. L250-L263 ◽  
Author(s):  
Nilam S. Mangalmurti ◽  
Jessica L. Friedman ◽  
Liang-Chuan Wang ◽  
Donna Stolz ◽  
Geetha Muthukumaran ◽  
...  
Keyword(s):  
Advanced Glycation End Products ◽  
Endothelial Activation ◽  
Advanced Glycation ◽  
Glycation End Products ◽  
End Products ◽  
Lung Endothelium ◽  
Rage Expression ◽  
Rbc Transfusion

The receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor implicated in multiple disease states. Although RAGE is expressed on systemic vascular endothelium, the expression and function of RAGE on lung endothelium has not been studied. Utilizing in vitro (human) and in vivo (mouse) models, we established the presence of RAGE on lung endothelium. Because RAGE ligands can induce the expression of RAGE and stored red blood cells express the RAGE ligand Nε-carboxymethyl lysine, we investigated whether red blood cell (RBC) transfusion would augment RAGE expression on endothelium utilizing a syngeneic model of RBC transfusion. RBC transfusion not only increased lung endothelial RAGE expression but enhanced lung inflammation and endothelial activation, since lung high mobility group box 1 and vascular cell adhesion molecule 1 expression was elevated following transfusion. These effects were mediated by RAGE, since endothelial activation was absent in RBC-transfused RAGE knockout mice. Thus, RAGE is inducibly expressed on lung endothelium, and one functional consequence of RBC transfusion is increased RAGE expression and endothelial activation.

scholarly journals Senescence Phenomena and Metabolic Alteration in Mesenchymal Stromal Cells from a Mouse Model of Rett Syndrome

2019 ◽  
Vol 20 (10) ◽  
pp. 2508 ◽  
Author(s):  
Tiziana Squillaro ◽  
Nicola Alessio ◽  
Stefania Capasso ◽  
Giovanni Di Bernardo ◽  
Mariarosa Melone ◽  
...  
Keyword(s):  
Stem Cell ◽  
Mouse Model ◽  
Cell Fate ◽  
Rett Syndrome ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Cell Biology ◽  
Neurodevelopmental Disorder ◽  
Expression Patterns ◽  
The Government

Chromatin modifiers play a crucial role in maintaining cell identity through modulation of gene expression patterns. Their deregulation can have profound effects on cell fate and functions. Among epigenetic regulators, the MECP2 protein is particularly attractive. Mutations in the Mecp2 gene are responsible for more than 90% of cases of Rett syndrome (RTT), a progressive neurodevelopmental disorder. As a chromatin modulator, MECP2 can have a key role in the government of stem cell biology. Previously, we showed that deregulated MECP2 expression triggers senescence in mesenchymal stromal cells (MSCs) from (RTT) patients. Over the last few decades, it has emerged that senescent cells show alterations in the metabolic state. Metabolic changes related to stem cell senescence are particularly detrimental, since they contribute to the exhaustion of stem cell compartments, which in turn determine the falling in tissue renewal and functionality. Herein, we dissect the role of impaired MECP2 function in triggering senescence along with other senescence-related aspects, such as metabolism, in MSCs from a mouse model of RTT. We found that MECP2 deficiencies lead to senescence and impaired mitochondrial energy production. Our results support the idea that an alteration in mitochondria metabolic functions could play an important role in the pathogenesis of RTT.

scholarly journals MeCP2 binds to non-CG methylated DNA as neurons mature, influencing transcription and the timing of onset for Rett syndrome

2015 ◽  
Vol 112 (17) ◽  
pp. 5509-5514 ◽  
Author(s):  
Lin Chen ◽  
Kaifu Chen ◽  
Laura A. Lavery ◽  
Steven Andrew Baker ◽  
Chad A. Shaw ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Rett Syndrome ◽  
Dna Sequences ◽  
Neurodevelopmental Disorder ◽  
Adult Brain ◽  
Gene Encoding ◽  
Dna Elements ◽  
Timing Of Onset

Epigenetic mechanisms, such as DNA methylation, regulate transcriptional programs to afford the genome flexibility in responding to developmental and environmental cues in health and disease. A prime example involving epigenetic dysfunction is the postnatal neurodevelopmental disorder Rett syndrome (RTT), which is caused by mutations in the gene encoding methyl-CpG binding protein 2 (MeCP2). Despite decades of research, it remains unclear how MeCP2 regulates transcription or why RTT features appear 6–18 months after birth. Here we report integrated analyses of genomic binding of MeCP2, gene-expression data, and patterns of DNA methylation. In addition to the expected high-affinity binding to methylated cytosine in the CG context (mCG), we find a distinct epigenetic pattern of substantial MeCP2 binding to methylated cytosine in the non-CG context (mCH, where H = A, C, or T) in the adult brain. Unexpectedly, we discovered that genes that acquire elevated mCH after birth become preferentially misregulated in mouse models of MeCP2 disorders, suggesting that MeCP2 binding at mCH loci is key for regulating neuronal gene expression in vivo. This pattern is unique to the maturing and adult nervous system, as it requires the increase in mCH after birth to guide differential MeCP2 binding among mCG, mCH, and nonmethylated DNA elements. Notably, MeCP2 binds mCH with higher affinity than nonmethylated identical DNA sequences to influence the level of Bdnf, a gene implicated in the pathophysiology of RTT. This study thus provides insight into the molecular mechanism governing MeCP2 targeting and sheds light on the delayed onset of RTT symptoms.

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