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 Whole brain delivery of an instability-proneMecp2transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

2019 ◽  
Author(s):  
Mirko Luoni ◽  
Serena Giannelli ◽  
Marzia Indrigo ◽  
Antonio Niro ◽  
Luca Massimino ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Rett Syndrome ◽  
Protein Translation ◽  
Mutant Mice ◽  
Severe Toxicity ◽  
Male And Female ◽  
Protein Levels ◽  
Mecp2 Protein ◽  
The Brain

AbstractRett syndrome (RTT) 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 sinceMECP2is expressed throughout the brain and its duplication leads to severe neurological conditions as well. However, the recent introduction of AAV-PHP.eB, an engineered capsid with an unprecedented efficiency in crossing the blood-brain barrier upon intravenous injection, has provided an invaluable vehicle for gene transfer in the mouse nervous system. Herein, we use AAV-PHP.eB to deliver an instability-proneMecp2(iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viralMecp2transgene, limits supraphysiological Mecp2 protein levels in transduced neural tissues. Intravenous injections of the PHP.eB-iMecp2virus in symptomatic male and femaleMecp2mutant mice significantly ameliorated the disease progression with improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling. Remarkably, PHP.eB-iMecp2administration did not result in severe toxicity effects either in femaleMecp2mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated maleMecp2mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of theiMecp2cassette provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain. This combination defines a novel viral system with significant therapeutic efficacy and increased safety which can contribute to overcome the hurdles that are delaying clinical applications of gene therapy for RTT.One Sentence SummaryGlobal brain transduction of the instability-proneMecp2transgene by systemic AAV-PHP.eB administration is both safe and effective in protecting male and femaleMecp2mutant mice from the RTT disease phenotype.

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 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 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.

Early Defects of GABAergic Synapses in the Brain Stem of a MeCP2 Mouse Model of Rett Syndrome

2008 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
L. Medrihan ◽  
E. Tantalaki ◽  
G. Aramuni ◽  
V. Sargsyan ◽  
I. Dudanova ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Brain Stem ◽  
Rett Syndrome ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Neurodevelopmental Disorder ◽  
Therapeutic Interventions ◽  
Ventrolateral Medulla ◽  
Diagnostic Tools ◽  
The Brain

Rett syndrome is a neurodevelopmental disorder caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2) and represents the leading genetic cause for mental retardation in girls. MeCP2-mutant mice have been generated to study the molecular mechanisms of the disease. It was suggested that an imbalance between excitatory and inhibitory neurotransmission is responsible for the behavioral abnormalities, although it remained largely unclear which synaptic components are affected and how cellular impairments relate to the time course of the disease. Here, we report that MeCP2 KO mice present an imbalance between inhibitory and excitatory synaptic transmission in the ventrolateral medulla already at postnatal day 7. Focusing on the inhibitory synaptic transmission we show that GABAergic, but not glycinergic, synaptic transmission is strongly depressed in MeCP2 KO mice. These alterations are presumably due to both decreased presynaptic γ-aminobutyric acid (GABA) release with reduced levels of the vesicular inhibitory transmitter transporter and reduced levels of postsynaptic GABAA-receptor subunits α2 and α4. Our data indicate that in the MeCP2 −/y mice specific synaptic molecules and signaling pathways are impaired in the brain stem during early postnatal development. These observations mandate the search for more refined diagnostic tools and may provide a rationale for the timing of future therapeutic interventions in Rett patients.

scholarly journals 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome

2012 ◽  
Vol 112 (5) ◽  
pp. 704-710 ◽  
Author(s):  
Rebecca A. Johnson ◽  
Maxine Lam ◽  
Antonio M. Punzo ◽  
Hongda Li ◽  
Benjamin R. Lin ◽  
...  
Keyword(s):  
Disease Progression ◽  
Rett Syndrome ◽  
Developmental Disorder ◽  
Body Weight Loss ◽  
Autism Spectrum ◽  
Mutant Mice ◽  
Disease Symptoms ◽  
Neuronal Nuclei ◽  
Conditional Deletion ◽  
The Brain

Rett syndrome (RTT), caused by mutations in the methyl-CpG binding protein 2 gene ( MECP2), is a debilitating autism spectrum developmental disorder predominantly affecting females. Mecp2 mutant mice have reduced levels of brain-derived neurotrophic factor (BDNF) in the brain; conditional deletion and overexpression of BDNF in the brain accelerates and slows, respectively, disease progression in Mecp2 mutant mice. Thus we tested the hypothesis that 7,8-dihydroxyflavone (7,8-DHF), a small molecule reported to activate the high affinity BDNF receptor (TrkB) in the CNS, would attenuate disease progression in Mecp2 mutant mice. Following weaning, 7,8-DHF was administered in drinking water throughout life. Treated mutant mice lived significantly longer compared with untreated mutant littermates (80 ± 4 and 66 ± 2 days, respectively). 7,8-DHF delayed body weight loss, increased neuronal nuclei size and enhanced voluntary locomotor (running wheel) distance in Mecp2 mutant mice. In addition, administration of 7,8-DHF partially improved breathing pattern irregularities and returned tidal volumes to near wild-type levels. Thus although the specific mechanisms are not completely known, 7,8-DHF appears to reduce disease symptoms in Mecp2 mutant mice and may have potential as a therapeutic treatment for RTT patients.

scholarly journals MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021 ◽  
Vol 12 ◽  
Author(s):  
Katrina V. Good ◽  
John B. Vincent ◽  
Juan Ausió
Keyword(s):  
Rett Syndrome ◽  
Neuronal Development ◽  
Neurodevelopmental Disorder ◽  
Epigenetic Mark ◽  
Initial Development ◽  
Genetic Ablation ◽  
Developmental Regression ◽  
The Stability ◽  
The Brain

Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

scholarly journals The Molecular Functions of MeCP2 in Rett Syndrome Pathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Osman Sharifi ◽  
Dag H. Yasui
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Original Research ◽  
Novel Treatments ◽  
Conflicting Evidence ◽  
Mecp2 Protein ◽  
Culture Models ◽  
Biologic Function ◽  
Cell Culture Models

MeCP2 protein, encoded by the MECP2 gene, binds to DNA and affects transcription. Outside of this activity the true range of MeCP2 function is still not entirely clear. As MECP2 gene mutations cause the neurodevelopmental disorder Rett syndrome in 1 in 10,000 female births, much of what is known about the biologic function of MeCP2 comes from studying human cell culture models and rodent models with Mecp2 gene mutations. In this review, the full scope of MeCP2 research available in the NIH Pubmed (https://pubmed.ncbi.nlm.nih.gov/) data base to date is considered. While not all original research can be mentioned due to space limitations, the main aspects of MeCP2 and Rett syndrome research are discussed while highlighting the work of individual researchers and research groups. First, the primary functions of MeCP2 relevant to Rett syndrome are summarized and explored. Second, the conflicting evidence and controversies surrounding emerging aspects of MeCP2 biology are examined. Next, the most obvious gaps in MeCP2 research studies are noted. Finally, the most recent discoveries in MeCP2 and Rett syndrome research are explored with a focus on the potential and pitfalls of novel treatments and therapies.

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 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.

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