scholarly journals A Plasma Proteomic Approach in Rett Syndrome: Classical versus Preserved Speech Variant

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Alessio Cortelazzo ◽  
Roberto Guerranti ◽  
Claudio De Felice ◽  
Cinzia Signorini ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Phenotypic Expression ◽  
Complement C3 ◽  
Plasma Proteome ◽  
Gene Encoding ◽  
Expression Variability ◽  
Proteomic Approach ◽  
Clinical Presentations ◽  
Alpha 1 Antitrypsin

Rett syndrome (RTT) is a progressive neurodevelopmental disorder mainly caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Although over 200 mutations types have been identified so far, nine of which the most frequent ones. A wide phenotypical heterogeneity is a well-known feature of the disease, with different clinical presentations, including the classical form and the preserved speech variant (PSV). Aim of the study was to unveil possible relationships between plasma proteome and phenotypic expression in two cases of familial RTT represented by two pairs of sisters, harbor the sameMECP2gene mutation while being dramatically discrepant in phenotype, that is, classical RTT versus PSV. Plasma proteome was analysed by 2-DE/MALDI-TOF MS. A significant overexpression of six proteins in the classical sisters was detected as compared to the PSV siblings. A total of five out of six (i.e., 83.3%) of the overexpressed proteins were well-known acute phase response (APR) proteins, including alpha-1-microglobulin, haptoglobin, fibrinogen beta chain, alpha-1-antitrypsin, and complement C3. Therefore, the examined RTT siblings pairs proved to be an important benchmark model to test the molecular basis of phenotypical expression variability and to identify potential therapeutic targets of the disease.

scholarly journals Effects ofω-3 Polyunsaturated Fatty Acids on Plasma Proteome in Rett Syndrome

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Claudio De Felice ◽  
Alessio Cortelazzo ◽  
Cinzia Signorini ◽  
Roberto Guerranti ◽  
Silvia Leoncini ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Polyunsaturated Fatty Acids ◽  
Rett Syndrome ◽  
Clinical Symptoms ◽  
Neurodevelopmental Disorder ◽  
Plasma Proteome ◽  
Omega 3 ◽  
Gene Encoding ◽  
Mecp2 Protein ◽  
Novel Therapeutic Strategies

The mechanism of action of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) is only partially known. Prior reports suggest a partial rescue of clinical symptoms and oxidative stress (OS) alterations followingω-3 PUFAs supplementation in patients with Rett syndrome (RTT), a devastating neurodevelopmental disorder with transient autistic features, affecting almost exclusively females and mainly caused by sporadic mutations in the gene encoding the methyl CpG binding protein 2 (MeCP2) protein. Here, we tested the hypothesis thatω-3 PUFAs may modify the plasma proteome profile in typical RTT patients withMECP2mutations and classic phenotype. A total of 24 RTT girls at different clinical stages were supplemented withω-3 PUFAs as fish oil for 12 months and compared to matched healthy controls. The expression of 16 proteins, mainly related to acute phase response (APR), was changed at the baseline in the untreated patients. Followingω-3 PUFAs supplementation, the detected APR was partially rescued, with the expression of 10 out of 16 (62%) proteins being normalized.ω-3 PUFAs have a major impact on the modulation of the APR in RTT, thus providing new insights into the role of inflammation in autistic disorders and paving the way for novel therapeutic strategies.

scholarly journals Plasma-Based Proteomics Profiling of Patients with Hyperthyroidism after Antithyroid Treatment

Molecules ◽  
2020 ◽  
Vol 25 (12) ◽  
pp. 2831
Author(s):  
Afshan Masood ◽  
Hicham Benabdelkamel ◽  
Aishah A. Ekhzaimy ◽  
Assim A. Alfadda
Keyword(s):  
Apolipoprotein A1 ◽  
Mitogen Activated Protein Kinase ◽  
Plasma Proteome ◽  
Gamma Chain ◽  
Hyperthyroid State ◽  
Proteomic Approach ◽  
Significant Difference ◽  
Mitogen Activated Protein ◽  
Alpha 1 Antitrypsin ◽  
Altered Proteins

Thyroid hormones critically modulate body homeostasis and haemostasis by regulating energy and metabolism. Previous studies have focused on individual pathways or proteins that are affected by increases in thyroid hormone levels, while an overall plasma proteomic signature of this increased level is lacking. Herein, an integrated untargeted proteomic approach with network analysis was used to identify changes in circulating proteins in the plasma proteome between hyperthyroid and euthyroid states. Plasma from 10 age-matched subjects at baseline (hyperthyroid) and post treatment with carbimazole (euthyroid) was compared by difference gel electrophoresis (DIGE) and matrix-assisted laser desorption/ionization time of flight (MALDI TOF) mass spectrometry (MS). A total of 20 proteins were identified with significant difference in abundance (analysis of variance (ANOVA) test, p ≤ 0.05; fold-change ≥ 1.5) between the two states (12 increased and 8 decreased in abundance in the hyperthyroid state). Twelve protein spots corresponding to ten unique proteins were significantly more abundant in the hyperthyroid state compared with the euthyroid state. These increased proteins were haptoglobin (HP), hemopexin (HPX), clusterin (CLU), apolipoprotein L1 (APOL1), alpha-1-B glycoprotein (A1BG), fibrinogen gamma chain (FGG), Ig alpha-1 chain C region (IGHA1), complement C6 (C6), leucine rich alpha 2 glycoprotein (LRG1), and carboxypeptidase N catalytic chain (CPN1). Eight protein spots corresponding to six unique proteins were significantly decreased in abundance in the hyperthyroid samples compared with euthyroid samples. These decreased proteins were apolipoprotein A1 (APOA1), inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4), plasminogen (PLG), alpha-1 antitrypsin (SERPINA1), fibrinogen beta chain (FGB), and complement C1r subcomponent (C1R). The differentially abundant proteins were investigated by ingenuity pathway analysis (IPA). The network pathway identified related to infectious disease, inflammatory disease, organismal injury and abnormalities, and the connectivity map focused around two central nodes, namely the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and p38 mitogen-activated protein kinase (MAPK) pathways. The plasma proteome of patients with hyperthyroidism revealed differences in the abundance of proteins involved in acute phase response signaling, and development of a hypercoagulable and hypofibrinolytic state. Our findings enhance our existing knowledge of the altered proteins and associated biochemical pathways in hyperthyroidism.

scholarly journals Inflammatory Lung Disease in Rett Syndrome

2014 ◽  
Vol 2014 ◽  
pp. 1-15 ◽  
Author(s):  
Claudio De Felice ◽  
Marcello Rossi ◽  
Silvia Leoncini ◽  
Glauco Chisci ◽  
Cinzia Signorini ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Upper Airway ◽  
Redox Status ◽  
Null Mouse ◽  
Gene Encoding ◽  
Respiratory Dysfunction ◽  
Lung Histology ◽  
Reduced And Oxidized Glutathione ◽  
Major Target

Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly linked to mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Respiratory dysfunction, historically credited to brainstem immaturity, represents a major challenge in RTT. Our aim was to characterize the relationships between pulmonary gas exchange abnormality (GEA), upper airway obstruction, and redox status in patients with typical RTT (n= 228) and to examine lung histology in aMecp2-null mouse model of the disease. GEA was detectable in ~80% (184/228) of patients versus ~18% of healthy controls, with “high” (39.8%) and “low” (34.8%) patterns dominating over “mixed” (19.6%) and “simple mismatch” (5.9%) types. Increased plasma levels of non-protein-bound iron (NPBI), F2-isoprostanes (F2-IsoPs), intraerythrocyte NPBI (IE-NPBI), and reduced and oxidized glutathione (i.e., GSH and GSSG) were evidenced in RTT with consequently decreased GSH/GSSG ratios. Apnea frequency/severity was positively correlated with IE-NPBI, F2-IsoPs, and GSSG and negatively with GSH/GSSG ratio. A diffuse inflammatory infiltrate of the terminal bronchioles and alveoli was evidenced in half of the examinedMecp2-mutant mice, well fitting with the radiological findings previously observed in RTT patients. Our findings indicate that GEA is a key feature of RTT and that terminal bronchioles are a likely major target of the disease.

scholarly journals Whole brain delivery of an instability-prone Mecp2 transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Tina Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Protein Translation ◽  
Mutant Mice ◽  
Gene Encoding ◽  
Strong Immune Response ◽  
Intravenous Injections ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

Rett syndrome is an incurable neurodevelopmental disorder caused by mutations in the gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. Herein, we use the AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic Mecp2 mutant mice significantly improved locomotor activity, lifespan and gene expression normalization. Remarkably, PHP.eB-iMecp2 administration was well tolerated in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of iMecp2 provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain.

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 Immune Dysfunction in Rett Syndrome Patients Revealed by High Levels of Serum Anti-N(Glc) IgM Antibody Fraction

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Anna Maria Papini ◽  
Francesca Nuti ◽  
Feliciana Real-Fernandez ◽  
Giada Rossi ◽  
Caterina Tiberi ◽  
...  
Keyword(s):  
Immune System ◽  
Rett Syndrome ◽  
Pervasive Developmental Disorders ◽  
Developmental Disorders ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Antibody Recognition ◽  
Forkhead Box ◽  
Significant Difference

Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n=53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n=82) and healthy age-matched controls (n=29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a syntheticN-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P=0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.

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 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.

scholarly journals Quantitative Proteomic Analysis of Plasma after Remote Ischemic Conditioning in a Rhesus Monkey Ischemic Stroke Model

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1164
Author(s):  
Siying Song ◽  
Linlin Guo ◽  
Di Wu ◽  
Jingfei Shi ◽  
Yunxia Duan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Rhesus Monkey ◽  
Proteomic Analysis ◽  
Complement C3 ◽  
Protective Effects ◽  
Plasma Proteome ◽  
Remote Ischemic Conditioning ◽  
Ischemic Conditioning ◽  
Metabolism Regulation ◽  
Induced Changes

Background: Animal and clinical studies have shown that remote ischemic conditioning (RIC) has protective effects for cerebral vascular diseases, with induced humoral factor changes in the peripheral blood. However, many findings are heterogeneous, perhaps due to differences in the RIC intervention schemes, enrolled populations, and sample times. This study aimed to examine the RIC-induced changes in the plasma proteome using rhesus monkey models of strokes. Methods: Two adult rhesus monkeys with autologous blood clot-induced middle cerebral artery (MCA) occlusion underwent RIC interventions twice a week for five consecutive weeks. Each RIC treatment included five cycles of five minutes of ischemia alternating with five minutes of reperfusion of the forearm. The blood samples were taken from the median cubital vein of the monkeys at baseline and immediately after each week’s RIC stimulus. The plasma samples were isolated for a proteomic analysis using mass spectrometry (MS). Results: Several proteins related to lipid metabolism (Apolipoprotein A-II and Apolipoprotein C-II), coagulation (Fibrinogen alpha chain and serpin), immunoinflammatory responses (complement C3 and C1), and endovascular hemostasis (basement membrane-specific heparan sulfate proteoglycan) were significantly modulated after the RIC intervention. Many of these induced changes, such as in the lipid metabolism regulation and anticoagulation responses, starting as early as two weeks following the RIC intervention. The complementary activation and protection of the endovascular cells occurred more than three weeks postintervention. Conclusions: Multiple protective effects were induced by RIC and involved lipid metabolism regulation (anti-atherogenesis), anticoagulation (antithrombosis), complement activation, and endovascular homeostasis (anti-inflammation). In conclusion, this study indicates that RIC results in significant modulations of the plasma proteome. It also provides ideas for future research and screening targets.

scholarly journals Association between EFHD2 gene polymorphisms and schizophrenia among the Han population in northern China

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052093280
Author(s):  
Meng Gao ◽  
Kuo Zeng ◽  
Ya Li ◽  
Yong-ping Liu ◽  
Xi Xia ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Neurodevelopmental Disorder ◽  
Haplotype Frequency ◽  
Northern China ◽  
Polymorphism Analysis ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Gene Encoding ◽  
Frequency Distributions ◽  
And Control

Objective Schizophrenia is a severe neurodevelopmental disorder with a complex genetic and environmental etiology. The gene encoding EF-hand domain-containing protein D2 ( EFHD2) may be a genetic risk locus for schizophrenia. Methods We genotyped four EFHD2 single-nucleotide polymorphisms (281 schizophrenia cases [SCZ], 321 controls) from northern Chinese Han individuals using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism analysis. Differences existed in genotype, allele, and haplotype frequency distributions between SCZ and control groups. Results The rs2473357 genotype and allele frequency distributions differed between SCZ and controls; however, this difference disappeared after Bonferroni correction. Differences in rs2473357 genotype and allele frequency distributions between SCZ and controls were more pronounced in men than in women. The G allele increased schizophrenia risk (odds ratio = 1.807, 95% confidence interval = 1.164–2.803). Among six haplotypes (G–, A–, G-insC, A-C, G-C, and G-T), the G– haplotype frequency distribution differed between SCZ and controls in women; the A-C and G-C haplotype frequency distributions differed between SCZ and controls in men. Conclusions EFHD2 may be involved in schizophrenia. Sex differences in EFHD2 genotype and allele frequency distributions existed among schizophrenia patients. Further research is needed to determine the role of EFHD2 in schizophrenia.

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