scholarly journals Convergent Cerebrospinal Fluid Proteomes and Metabolic Ontologies in Humans and Animal Models of Rett Syndrome

2021 ◽  
Author(s):  
Stephanie A Zlatic ◽  
Duc Duong ◽  
Kamal KE Gadalla ◽  
Brenda Murage ◽  
Lingyan Ping ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Rett Syndrome ◽  
Roc Analysis ◽  
Operating Characteristic ◽  
Neurodevelopmental Disorder ◽  
Loss Of Function ◽  
Pyruvate Metabolism ◽  
Brain Transcriptome ◽  
Ontological Categories ◽  
Discriminatory Capacity

MECP2 loss-of-function mutations cause Rett syndrome, a disorder that results from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome in Rett syndrome cerebrospinal fluid (CSF) across vertebrates. We identified a consensus proteome and ontological categories shared across Rett syndrome cerebrospinal fluid (CSF) from three species, including humans. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, as well as synapse compartments. We used these prioritized and shared ontologies to select analytes for orthogonal quantification. These studies independently validated our proteome and ontologies. Ontologically selected CSF hits had genotypic discriminatory capacity as determined by Receiver Operating Characteristic (ROC) analysis and distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose that Mecp2 mutant CSF proteomes and ontologies inform novel putative mechanisms and biomarkers of disease. We suggest that Rett syndrome is a metabolic disorder impacting synapse function.

scholarly journals Sphingolipid Metabolism Perturbations in Rett Syndrome

Metabolites ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 221 ◽  
Author(s):  
Cappuccio ◽  
Donti ◽  
Pinelli ◽  
Bernardo ◽  
Bravaccio ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Metabolic Profiling ◽  
Neurodevelopmental Disorder ◽  
Sphingolipid Metabolism ◽  
Tandem Mass ◽  
Mecp2 Gene ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Blood Samples ◽  
Disease Biomarkers

Rett syndrome is a severe neurodevelopmental disorder affecting mostly females and is caused by loss-of-function mutations in the MECP2 gene that encoded the methyl-CpG-binding protein 2. The pathogenetic mechanisms of Rett syndrome are not completely understood and metabolic derangements are emerging as features of Rett syndrome. We performed a semi-quantitative tandem mass spectrometry-based analysis that measured over 900 metabolites on blood samples from 14 female subjects with Rett syndrome carrying MECP2 mutations. The metabolic profiling revealed alterations in lipids, mostly involved in sphingolipid metabolism, and sphinganine/sphingosine, that are known to have a neurotrophic role. Further investigations are required to understand the mechanisms underlying such perturbations and their significance in the disease pathogenesis. Nevertheless, these metabolites are attractive for studies on the disease pathogenesis and as potential disease biomarkers.

scholarly journals Cyclin-Dependent Kinase-Like 5 (CDKL5): Possible Cellular Signalling Targets and Involvement in CDKL5 Deficiency Disorder

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Syouichi Katayama ◽  
Noriyuki Sueyoshi ◽  
Tetsuya Inazu ◽  
Isamu Kameshita
Keyword(s):  
Catalytic Activity ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Cyclin Dependent Kinase ◽  
Loss Of Function ◽  
Neuronal Function ◽  
Transcriptional Mapping ◽  
Target Molecules ◽  
New Treatment ◽  
The Relationship

Cyclin-dependent kinase-like 5 (CDKL5, also known as STK9) is a serine/threonine protein kinase originally identified in 1998 during a transcriptional mapping project of the human X chromosome. Thereafter, a mutation in CDKL5 was reported in individuals with the atypical Rett syndrome, a neurodevelopmental disorder, suggesting that CDKL5 plays an important regulatory role in neuronal function. The disease associated with CDKL5 mutation has recently been recognised as CDKL5 deficiency disorder (CDD) and has been distinguished from the Rett syndrome owing to its symptomatic manifestation. Because CDKL5 mutations identified in patients with CDD cause enzymatic loss of function, CDKL5 catalytic activity is likely strongly associated with the disease. Consequently, the exploration of CDKL5 substrate characteristics and regulatory mechanisms of its catalytic activity are important for identifying therapeutic target molecules and developing new treatment. In this review, we summarise recent findings on the phosphorylation of CDKL5 substrates and the mechanisms of CDKL5 phosphorylation and dephosphorylation. We also discuss the relationship between changes in the phosphorylation signalling pathways and the Cdkl5 knockout mouse phenotype and consider future prospects for the treatment of mental and neurological disease associated with CDKL5 mutations.

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 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 Molecular Context-Dependent Effects Induced by Rett Syndrome-Associated Mutations in MeCP2

Biomolecules ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. 1533 ◽  
Author(s):  
David Ortega-Alarcon ◽  
Rafael Claveria-Gimeno ◽  
Sonia Vega ◽  
Olga C. Jorge-Torres ◽  
Manel Esteller ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Neuronal Development ◽  
Binding Protein ◽  
Neurodevelopmental Disorder ◽  
Intrinsically Disordered Protein ◽  
Loss Of Function ◽  
Intrinsically Disordered ◽  
Biophysical Study ◽  
Molecular Context ◽  
Functional Features

Methyl-CpG binding protein 2 (MeCP2) is a transcriptional regulator and a chromatin-binding protein involved in neuronal development and maturation. Loss-of-function mutations in MeCP2 result in Rett syndrome (RTT), a neurodevelopmental disorder that is the main cause of mental retardation in females. MeCP2 is an intrinsically disordered protein (IDP) constituted by six domains. Two domains are the main responsible elements for DNA binding (methyl-CpG binding domain, MBD) and recruitment of gene transcription/silencing machinery (transcription repressor domain, TRD). These two domains concentrate most of the RTT-associated mutations. R106W and R133C are associated with severe and mild RTT phenotype, respectively. We have performed a comprehensive characterization of the structural and functional impact of these substitutions at molecular level. Because we have previously shown that the MBD-flanking disordered domains (N-terminal domain, NTD, and intervening domain, ID) exert a considerable influence on the structural and functional features of the MBD (Claveria-Gimeno, R. et al. Sci Rep. 2017, 7, 41635), here we report the biophysical study of the influence of the protein scaffold on the structural and functional effect induced by these two RTT-associated mutations. These results represent an example of how a given mutation may show different effects (sometimes opposing effects) depending on the molecular context.

scholarly journals Developmental loss of MeCP2 from VIP interneurons impairs cortical function and behavior

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
James M Mossner ◽  
Renata Batista-Brito ◽  
Rima Pant ◽  
Jessica A Cardin
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Critical Role ◽  
Cell Types ◽  
Loss Of Function ◽  
Cortical Function ◽  
Behavioral Phenotypes ◽  
Pathophysiological Role ◽  
And Function ◽  
And Behavior

Rett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MECP2. Mutations of Mecp2 that are restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a pathophysiological role for inhibitory interneurons. Recent work has suggested that vasoactive intestinal peptide-expressing (VIP) interneurons may play a critical role in the proper development and function of cortical circuits, making them a potential key point of vulnerability in neurodevelopmental disorders. However, little is known about the role of VIP interneurons in Rett Syndrome. Here we find that loss of MeCP2 specifically from VIP interneurons replicates key neural and behavioral phenotypes observed following global Mecp2 loss of function.

scholarly journals Wide phenotypic spectrum of human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations

2020 ◽  
Author(s):  
Rebecca SF Mok ◽  
Wenbo Zhang ◽  
Taimoor I Sheikh ◽  
Isabella R Fernandes ◽  
Leah C DeJong ◽  
...  
Keyword(s):  
Stem Cell ◽  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Synaptic Function ◽  
Proper Function ◽  
Loss Of Function ◽  
Electrode Arrays ◽  
Burst Frequency ◽  
Wide Range ◽  
Excitatory Neurons

ABSTRACTRett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene methyl-CpG-binding protein 2 (MECP2) that is a global transcriptional regulator. Mutations in the methyl-binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA required for proper function in the brain. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD in comparison to MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cell lines. L124W induced excitatory neurons expressed stable protein, exhibited only increased input resistance and impaired voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to reduced dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more pronounced morphological and electrophysiological phenotypes, exhibiting decreased soma area, dendrite length, capacitance and excitatory synaptic function. We examined development and maturation of excitatory neural networks using micro-electrode arrays to detect alterations in RTT connectivity. The L124W neurons had no detectable changes in network circuitry features, in contrast to MECP2 null neurons that suffered a significant change in synchronous network burst frequency and a transient extension of network burst duration. Our results from stem cell-derived RTT excitatory neurons reveal a wide range of morphological, electrophysiological and circuitry phenotypes that reflect the severity of the MECP2 mutation.

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization

2015 ◽  
Vol 396 (11) ◽  
pp. 1233-1240 ◽  
Author(s):  
Lucia Ciccoli ◽  
Claudio De Felice ◽  
Silvia Leoncini ◽  
Cinzia Signorini ◽  
Alessio Cortelazzo ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Morphological Changes ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Current Evidence ◽  
Loss Of Function ◽  
Beneficial Effects ◽  
Spectrum Disorders

Abstract In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a ‘model’ condition for autism spectrum disorders.

scholarly journals Distinct contributions of three GABAergic interneuron populations to a mouse model of Rett Syndrome

2017 ◽  
Author(s):  
James M. Mossner ◽  
Renata Batista-Brito ◽  
Rima Pant ◽  
Jessica A. Cardin
Keyword(s):  
Rett Syndrome ◽  
Neurodevelopmental Disorder ◽  
Cell Types ◽  
Gabaergic Interneuron ◽  
Loss Of Function ◽  
Behavioral Phenotypes ◽  
Motor Behaviors ◽  
Marble Burying ◽  
And Performance ◽  
The Brain

AbstractBackgroundRett Syndrome is a devastating neurodevelopmental disorder resulting from mutations in the gene MeCP2. MeCP2 is a transcriptional regulator active in many cell types throughout the brain. However, mutations of MeCP2 restricted to GABAergic cell types largely replicate the behavioral phenotypes associated with mouse models of Rett Syndrome, suggesting a key role for inhibitory interneurons in the pathophysiology underlying this disorder.MethodsWe generated conditional deletions of MeCP2 from each of three major classes of GABAergic interneurons, the parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP)-expressing cells, along with a pan-interneuron deletion from all three GABAergic populations. We examined seizure incidence, mortality, and performance on several key behavioral assays.ResultsWe find that each interneuron class makes a contribution to the seizure phenotype associated with Rett Syndrome. PV, SOM, and VIP interneurons made partially overlapping contributions to deficits in motor behaviors. We find little evidence for elevated anxiety associated with any of the conditional deletions. However, MeCP2 deletion from VIP interneurons causes a unique deficit in marble burying. Furthermore, VIP interneurons make a distinct contribution to deficits in social behavior.ConclusionsWe find an unanticipated contribution of VIP interneuron dysfunction to the MeCP2 loss-of-function model of Rett Syndrome. Together, our findings suggest a complex interaction between GABAergic dysfunction and behavioral phenotypes in this neurodevelopmental disorder.

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