• Autism spectrum disorders
• Cerebellum
• Fmr1
• Mecp2
• Nlgn3/4
• Purkinje neurons
• Tsc1/2

• Animals
• Autism Spectrum Disorder/genetics
• Autism Spectrum Disorder/pathology
• Autism Spectrum Disorder/physiopathology
• Cerebellum/physiopathology
• Cerebellum/pathology
• Disease Models, Animal
• Models, Genetic

• Array comparative genomic hybridization
• Case report
• Methyl-CpG-binding protein 2
• Neurodevelopmental Delay
• Xq28 duplication

• Deep brain stimulation
• Fear memory
• Fornix
• Hippocampus
• Neurogenesis
• Rett syndrome

• Mice
• Animals
• Rett Syndrome/genetics
• Rett Syndrome/therapy
• Brain-Derived Neurotrophic Factor/genetics
• Brain-Derived Neurotrophic Factor/metabolism
• Deep Brain Stimulation
• Vascular Endothelial Growth Factor A/metabolism
• Hippocampus/physiology
• Neurogenesis/physiology

• P50 HD103555 NICHD NIH HHS
• R01 NS100738 NINDS NIH HHS
• R56 NS100738 NINDS NIH HHS
• U54 HD083092 NICHD NIH HHS

• National Natural Science Foundation of China

• cell adhesion molecule L1
• methyl-CpG-binding protein 2
• nuclear import
• proteolytic processing

• Amyloid Precursor Protein Secretases
• Animals
• Aspartic Acid Endopeptidases
• HEK293 Cells
• Humans
• Methyl-CpG-Binding Protein 2/genetics
• Mice
• Neural Cell Adhesion Molecule L1/metabolism
• RNA, Small Interfering/genetics

Rett Syndrome (RTT) is a rare and severe X-linked developmental brain disorder that occurs primarily in females, with a ratio of 1:10.000. De novo mutations in the Methyl-CpG Binding protein 2 (MECP2) gene on the long arm of X chromosome are responsible for more than 95% cases of classical Rett. In the remaining cases (atypical Rett), other genes are involved such as the cyclin-dependent kinase-like 5 (CDKL5) and the forkhead box G1 (FOXG1). Duplications of the MECP2 locus cause MECP2 duplication syndrome (MDS) which concerns about 1% of male patients with intellectual disability. Sleep disorders are common in individuals with intellectual disability, while the prevalence in children is between 16 and 42%. Over 80% of individuals affected by RTT show sleep problems, with a higher prevalence in the first 7 years of life and some degree of variability in correlation to age and genotype. Abnormalities in circadian rhythm and loss of glutamate homeostasis play a key role in the development of these disorders. Sleep disorders, epilepsy, gastrointestinal problems characterize CDKL5 Deficiency Disorder (CDD). Sleep impairment is an area of overlap between RTT and MECP2 duplication syndrome along with epilepsy, regression and others. Sleep dysfunction and epilepsy are deeply linked. Sleep deprivation could be an aggravating factor of epilepsy and anti-comitial therapy could interfere in sleep structure. Epilepsy prevalence in atypical Rett syndrome with severe clinical phenotype is higher than in classical Rett syndrome. However, RTT present a significant lifetime risk of epilepsy too. Sleep disturbances impact on child's development and patients' families and the evidence for its management is still limited. The aim of this review is to analyze pathophysiology, clinical features, the impact on other comorbidities and the management of sleep disorders in Rett syndrome and Rett-related syndrome.

• CDKL5
• FOXG1
• MECP2
• Rett syndrome
• Rett-related disorders
• sleep disorders

• CDKL5
• Double mutation
• MECP2
• R.A.R.S. score
• Rett like syndrome

• PAMAM dendrimer
• Rett syndrome
• glutaminase
• microglia

Despite decades of research on Alzheimer disease, understanding the complexity of the genetic and molecular interactions involved in its pathogenesis remains far from our grasp. Methyl-CpG Binding Protein 2 (MeCP2) is an important epigenetic regulator enriched in the brain, and recent findings have implicated MeCP2 as a crucial player in Alzheimer disease. Here, we provide comprehensive insights into the pathophysiological roles of MeCP2 in Alzheimer disease. In particular, we focus on how the alteration of MeCP2 expression can impact Alzheimer disease through risk genes, amyloid-β and tau pathology, cell death and neurodegeneration, and cellular senescence. We suggest that Alzheimer disease can be adversely affected by upregulated MeCP2-dependent repression of risk genes (MEF2C, ADAM10, and PM20D1), increased tau accumulation, and neurodegeneration through neuronal cell death (excitotoxicity and apoptosis). In addition, we propose that the progression of Alzheimer disease could be caused by reduced MeCP2-mediated enhancement of astrocytic and microglial senescence and consequent glial SASP (senescence-associated secretory phenotype)-dependent neuroinflammation. We surmise that any imbalance in MeCP2 function would accelerate or cause Alzheimer disease pathogenesis, implying that MeCP2 may be a potential drug target for the treatment and prevention of Alzheimer disease.

• Alzheimer disease
• MeCP2
• Neurodegeneration
• Neuroinflammation
• Risk genes
• Senescence

Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.

• clinical trials
• glutamate toxicity
• interneurons
• preclinical modeling
• seizures
• sleep

• Animals
• Clinical Trials as Topic
• Diagnosis, Differential
• Disease Management
• Disease Susceptibility
• Epileptic Syndromes/diagnosis
• Epileptic Syndromes/etiology
• Epileptic Syndromes/therapy
• Humans
• Methyl-CpG-Binding Protein 2/genetics
• Methyl-CpG-Binding Protein 2/metabolism
• Mutation
• Outcome Assessment, Health Care
• Phenotype
• Protein Serine-Threonine Kinases/genetics
• Protein Serine-Threonine Kinases/metabolism
• Rett Syndrome/diagnosis
• Rett Syndrome/etiology
• Rett Syndrome/therapy
• Spasms, Infantile/diagnosis
• Spasms, Infantile/etiology
• Spasms, Infantile/therapy
• Translational Research, Biomedical

• R01 HD090884 NICHD NIH HHS

• AMPA receptor
• GABA(A) receptor
• Rett syndrome, oocytes
• epilepsy
• human brain tissue

• Apoptosis
• BIRC5
• Neuropathology
• Protocadherin 7
• Whole transcriptome sequencing

Rett syndrome (RTT) is a pervasive developmental disorder that is progressive and has no effective cure. Immune dysregulation, oxidative stress, and excess glutamate in the brain mediated by glial dysfunction have been implicated in the pathogenesis and worsening of symptoms of RTT. In this study, we investigated a new nanotherapeutic approach to target glia for attenuation of brain inflammation/injury both in vitro and in vivo using a Mecp2-null mouse model of Rett syndrome.

To determine whether inflammation and immune dysregulation were potential targets for dendrimer-based therapeutics in RTT, we assessed the immune response of primary glial cells from Mecp2-null and wild-type (WT) mice to LPS. Using dendrimers that intrinsically target activated microglia and astrocytes, we studied N-acetyl cysteine (NAC) and dendrimer-conjugated N-acetyl cysteine (D-NAC) effects on inflammatory cytokines by PCR and multiplex assay in WT vs Mecp2-null glia. Since the cysteine-glutamate antiporter (Xc⁻) is upregulated in Mecp2-null glia when compared to WT, the role of Xc⁻ in the uptake of NAC and l-cysteine into the cell was compared to that of D-NAC using BV2 cells in vitro. We then assessed the ability of D-NAC given systemically twice weekly to Mecp2-null mice to improve behavioral phenotype and lifespan.

We demonstrated that the mixed glia derived from Mecp2-null mice have an exaggerated inflammatory and oxidative stress response to LPS stimulation when compared to WT glia. Expression of Xc⁻ was significantly upregulated in the Mecp2-null glia when compared to WT and was further increased in the presence of LPS stimulation. Unlike NAC, D-NAC bypasses the Xc⁻ for cell uptake, increasing intracellular GSH levels while preventing extracellular glutamate release and excitotoxicity. Systemically administered dendrimers were localized in microglia in Mecp2-null mice, but not in age-matched WT littermates. Treatment with D-NAC significantly improved behavioral outcomes in Mecp2-null mice, but not survival.

These results suggest that delivery of drugs using dendrimer nanodevices offers a potential strategy for targeting glia and modulating oxidative stress and immune responses in RTT.

The online version of this article (10.1186/s12974-017-1004-5) contains supplementary material, which is available to authorized users.

• Glutamate
• Mecp2-null
• Microglia
• N-Acetyl cysteine
• PAMAM dendrimer
• Rett syndrome
• System Xc−

• Autism spectrum disorder
• Bergmann glia
• Cerebellum
• Dicer
• Embryonic development
• Granule cell progenitor
• MicroRNA
• Midbrain-hindbrain boundary

Rett syndrome is an extremely disabling X-linked nervous system disorder that mainly affects girls in early childhood and causes autism-like behavior, severe intellectual disability, seizures, sleep disturbances, autonomic instability, and other disorders due to mutations in the MeCP2 (methyl CpG-binding protein 2) transcription factor. The disorder targets synapses and synaptic plasticity and has been shown to disrupt the balance between glutamate excitatory synapses and GABAergic inhibitory synapses. In fact, it can be argued that Rett syndrome is primarily a disorder of synaptic plasticity and that agents that can correct this imbalance may have beneficial effects on brain development. This review briefly summarizes the link between disrupted synaptic plasticity mechanisms and Rett syndrome and early clinical trials that aim to target these abnormalities to improve the outcome for these severely disabled children.

• Glutamate
• Rett Syndrome
• X-linked

• Bax
• Caspase-3
• Hypoxia–ischemia
• Mitochondria
• Neonatal brain injury
• Neuronal pentraxin 1
• Neuronal pentraxin 2
• Oxygen glucose deprivation
• T2-weighted magnetic resonance imaging

Developing brain is highly susceptible to hypoxic-ischemic injury leading to severe neurological disabilities in surviving infants and children. Previously we reported induction of neuronal pentraxin 1 (NP1) in hypoxic-ischemic injury in neonatal brain and NP1 co-localization with the excitatory AMPA receptors GluR1 at the synaptic sites. However, how NP1 contributes to hypoxic-ischemic neuronal injury is not completely understood.

Here we report that extracellular secretion of NP1 is required for ischemic neuronal death. Primary cortical neurons at days in vitro (DIV) 12 were subjected to oxygen glucose deprivation (OGD), an in vitro model of ischemic stroke, for different time periods (2–8 h). Oxygen glucose deprivation showed characteristic morphological changes of dying cells, OGD time-dependent induction of NP1 (2-4-fold) and increased neuronal death. In contrast, the NP1-KO cortical neurons were healthy and showed no sign of dying cells under similar conditions. NP1gene silencing by NP1-specific small interfering RNA (NP1-siRNA) protected cortical neurons from OGD-induced death. Conditioned media (CM) collected from OGD exposed WT cortical cultures caused neurotoxicity when added to a subset of DIV 12 normoxia control WT cortical cultures. In contrast, CM from OGD-exposed NP1-KO cultures did not induce cell toxicity in control WT cultures, suggesting a role for extracellular NP1 in neuronal death. However, NP1-KO neurons, which showed normal neuronal morphology and protection against OGD, sustained enhanced death following incubation with CM from WT OGD-exposed cultures. Western blot analysis of OGD exposed WT CM showed temporal increase of NP1 protein levels in the CM. Most strikingly, in contrast to NP1-KO CM, incubation of normal cortical cultures with CM from OGD exposed NP2-KO cultures showed neurotoxicity similar to that observed with CM from OGD exposed WT neuronal cultures. Western immunoblotting further confirmed the increased presence of NP1 protein in OGD-exposed NP2-KO CM. Live immunofluorescence analysis show intense cell surface clustering of NP1 with AMPA GluR1 receptors.

Collectively, our results demonstrate that extracellular release of NP1 promote hypoxic-ischemic neuronal death possibly via surface clustering with GluR1 at synaptic sites and that NP1, not its family member NP2, is involved in the neuronal death mechanisms.

X-linked methyl-CpG binding protein 2 mutations can induce symptoms similar to those of Parkinson's disease and dopamine metabolism disorders, but the specific role of X-linked methyl-CpG binding protein 2 in the pathogenesis of Parkinson's disease remains unknown. In the present study, we used 6-hydroxydopamine-induced human neuroblastoma cell (SH-SY5Y cells) injury as a cell model of Parkinson's disease. The 6-hydroxydopamine (50 μmol/L) treatment decreased protein levels for both X-linked methyl-CpG binding protein 2 and tyrosine hydroxylase in these cells, and led to cell death. However, overexpression of X-linked methyl-CpG binding protein 2 was able to ameliorate the effects of 6-hydroxydopamine, it reduced 6-hydroxydopamine-induced apoptosis, and increased the levels of tyrosine hydroxylase in SH-SY5Y cells. These findings suggesting that X-linked methyl-CpG binding protein 2 may be a potential therapeutic target for the treatment of Parkinson's disease.

• 6-hydroxydopamine
• Parkinson's disease
• SH-SY5Y cells
• dopaminergic neurons
• grants-supported paper
• methyl-CpG-binding protein 2
• neural regeneration
• neurodegenerative diseases
• neuroregeneration
• tyrosine hydroxylase

• Mecp2
• Rett syndrome
• biomarkers
• glutamate
• sleep structure

• Apoptosis
• Cerebellum
• Ethanol
• Fetal
• MiR-29b
• MicroRNA
• Neurons
• PKR
• Signal Transduction

• Calcium
• Cytoplasmic ATP
• Epilepsy
• Hippocampus
• Imaging
• Rett syndrome

More than 90% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene that encodes the methyl-CpG-binding protein 2, a transcriptional modulator. Because MECP2 is subjected to X chromosome inactivation (XCI), girls with RTT either express the wild-type or mutant allele in each individual cell. To test the consequences of MECP2 mutations resulting from a genome-wide transcriptional dysregulation and to identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we carried out gene expression profiling of clonal populations derived from fibroblast primary cultures expressing exclusively either the wild-type or the mutant MECP2 allele. Clonal cultures were obtained from skin biopsy of three RTT patients carrying either a non-sense or a frameshift MECP2 mutation. For each patient, gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. Firstly, clustering analysis classified the RTT patients according to their genetic background and MECP2 mutation. Secondly, expression profiling by microarray analysis and quantitative RT-PCR indicated four up-regulated genes and five down-regulated genes significantly dysregulated in all our statistical analysis, including excellent potential candidate genes for the understanding of the pathophysiology of this neurodevelopmental disease. Thirdly, chromatin immunoprecipitation analysis confirmed MeCP2 binding to respective CpG islands in three out of four up-regulated candidate genes and sequencing of bisulphite-converted DNA indicated that MeCP2 preferentially binds to methylated-DNA sequences. Most importantly, the finding that at least two of these genes (BMCC1 and RNF182) were shown to be involved in cell survival and/or apoptosis may suggest that impaired MeCP2 function could alter the survival of neurons thus compromising brain function without inducing cell death.

• Animals
• Astrocytes/metabolism
• Brain/metabolism
• Brain/pathology
• Cells, Cultured
• Connexins/metabolism
• Culture Media, Conditioned
• Dendrites/metabolism
• Dendrites/pathology
• Disease Models, Animal
• Glutamic Acid/metabolism
• Glutaminase/antagonists & inhibitors
• Glutaminase/metabolism
• Hippocampus/metabolism
• Hippocampus/pathology
• Male
• Methyl-CpG-Binding Protein 2/deficiency
• Methyl-CpG-Binding Protein 2/genetics
• Methyl-CpG-Binding Protein 2/metabolism
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microglia/metabolism
• Neurons/metabolism
• Neurons/pathology
• Receptors, Glutamate/metabolism
• Rett Syndrome/metabolism
• Rett Syndrome/pathology
• Synapses/metabolism
• Synapses/pathology
• Gap Junction beta-1 Protein

• R01 HD064817 NICHD NIH HHS
• U54 HD079125 NICHD NIH HHS

• ischemic preconditioning
• microrna
• microarray
• mecp2
• tolerance

• Adolescent
• Adult
• Autistic Disorder
• Child
• Child, Preschool
• Disease Progression
• Erythrocytes/metabolism
• Erythrocytes/pathology
• F2-Isoprostanes/metabolism
• Female
• Genetic Predisposition to Disease
• Humans
• Intellectual Disability
• Iron/metabolism
• Methyl-CpG-Binding Protein 2/genetics
• Mutation
• Oxidative Stress
• Oxygen/metabolism
• Protein Carbonylation
• Rett Syndrome/genetics
• Rett Syndrome/pathology
• Rett Syndrome/physiopathology
• Ventilation-Perfusion Ratio

• plasticity
• injury
• fragile x syndrome
• rett syndrome
• hypoxia-ischemia
• nmda
• ampa
• periventricular leukomalacia

• Brain/pathology
• Brain/physiopathology
• Brain Injuries/pathology
• Brain Injuries/physiopathology
• Brain Injuries/therapy
• Child
• Fragile X Syndrome/pathology
• Fragile X Syndrome/physiopathology
• Fragile X Syndrome/therapy
• Humans
• Hypoxia-Ischemia, Brain/pathology
• Hypoxia-Ischemia, Brain/physiopathology
• Hypoxia-Ischemia, Brain/therapy
• Intellectual Disability/pathology
• Intellectual Disability/physiopathology
• Neuronal Plasticity
• Rett Syndrome/pathology
• Rett Syndrome/physiopathology
• Rett Syndrome/therapy

• R01 NS028208-18 NINDS NIH HHS
• R01 NS28208 NINDS NIH HHS
• R01 NS028208 NINDS NIH HHS
• P01 HD024448 NICHD NIH HHS
• P01 HD24448 NICHD NIH HHS