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1.
BMC Med Genet ; 20(1): 95, 2019 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-31151415

RESUMO

BACKGROUND: Tubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature. CASE PRESENTATIONS: Both patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features. CONCLUSION: This report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.


Assuntos
Predisposição Genética para Doença/genética , Mutação de Sentido Incorreto , Transtornos do Neurodesenvolvimento/genética , Tubulina (Proteína)/genética , Criança , Feminino , Humanos , Lactente , Masculino , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Índice de Gravidade de Doença
2.
Cell Mol Life Sci ; 76(15): 2899-2916, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31147750

RESUMO

Methylation of histone H3 lysine 36 (H3K36) plays crucial roles in the partitioning of chromatin to distinctive domains and the regulation of a wide range of biological processes. Trimethylation of H3K36 (H3K36me3) demarcates body regions of the actively transcribed genes, providing signals for modulating transcription fidelity, mRNA splicing and DNA damage repair; and di-methylation of H3K36 (H3K36me2) spreads out within large intragenic regions, regulating distribution of histone H3 lysine 27 trimethylation (H3K27me3) and possibly DNA methylation. These H3K36 methylation-mediated events are biologically crucial and controlled by different classes of proteins responsible for either 'writing', 'reading' or 'erasing' of H3K36 methylation marks. Deregulation of H3K36 methylation and related regulatory factors leads to pathogenesis of disease such as developmental syndrome and cancer. Additionally, recurrent mutations of H3K36 and surrounding histone residues are detected in human tumors, further highlighting the importance of H3K36 in biology and medicine. This review will elaborate on current advances in understanding H3K36 methylation and related molecular players during various chromatin-templated cellular processes, their crosstalks with other chromatin factors, as well as their deregulations in the diseased contexts.


Assuntos
Histonas/metabolismo , Neoplasias/patologia , Transtornos do Neurodesenvolvimento/patologia , Metilases de Modificação do DNA/metabolismo , Reparo do DNA , Histona Desmetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Humanos , Metilação , Neoplasias/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Processamento de RNA
3.
Int J Mol Sci ; 20(8)2019 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-31013990

RESUMO

Methyl CpG binding protein-2 (MeCP2) isoforms (E1 and E2) are important epigenetic regulators in brain cells. Accordingly, MeCP2 loss- or gain-of-function mutation causes neurodevelopmental disorders, including Rett syndrome (RTT), MECP2 duplication syndrome (MDS), and autism spectrum disorders (ASD). Within different types of brain cells, highest MeCP2 levels are detected in neurons and the lowest in astrocytes. However, our current knowledge of Mecp2/MeCP2 regulatory mechanisms remains largely elusive. It appears that there is a sex-dependent effect in X-linked MeCP2-associated disorders, as RTT primarily affects females, whereas MDS is found almost exclusively in males. This suggests that Mecp2 expression levels in brain cells might be sex-dependent. Here, we investigated the sex- and cell type-specific expression of Mecp2 isoforms in male and female primary neurons and astrocytes isolated from the murine forebrain. Previously, we reported that DNA methylation of six Mecp2 regulatory elements correlated with Mecp2 levels in the brain. We now show that in male brain cells, DNA methylation is significantly correlated with the transcript expression of these two isoforms. We show that both Mecp2 isoforms are highly expressed in male neurons compared to male astrocytes, with Mecp2e1 expressed at higher levels than Mecp2e2. Our data indicate that higher DNA methylation at the Mecp2 regulatory element(s) is associated with lower levels of Mecp2 isoforms in male astrocytes compared to male neurons.


Assuntos
Astrócitos/metabolismo , Metilação de DNA , Proteína 2 de Ligação a Metil-CpG/metabolismo , Neurônios/metabolismo , Animais , Astrócitos/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Ilhas de CpG , Modelos Animais de Doenças , Feminino , Genes Ligados ao Cromossomo X , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos , Transtornos do Neurodesenvolvimento/metabolismo , Transtornos do Neurodesenvolvimento/patologia , Neurônios/citologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
4.
DNA Cell Biol ; 38(5): 405-409, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30817175

RESUMO

The etiologies of most neurodevelopmental disorders, including autism spectrum disorder (ASD), remain incompletely understood. However, recent epidemiological and experimental data suggest that dysregulated maternal immune activation (MIA) can impede normal brain maturation and promote the development of autism-related phenotypes. Indeed, our studies and work by others demonstrate that offspring born to pregnant animals that were exposed to immune activators develop many of the defining behavioral features of ASD, including abnormalities in social preference, communicative impairments, and repetitive/stereotyped behaviors. Although mounting evidence implicates key roles for hyperactive gestational inflammatory responses in neurodevelopmental disorders, the specific immune pathways that provoke autism-related phenotypes remain poorly described. The microbiome is recognized as a key modulator of immune responses, and emerging studies suggest that microbiota composition is a pivotal regulator of central nervous system function and disease. There has been growing speculation that changes in human microflora diversity contribute at some level to the recent rise in autism incidence. This has largely stemmed from reports of dysbiosis and gastrointestinal inflammation in autistic individuals. Given these clinical findings and the well-described role of the microbiome in calibrating the immune system, our group and others have recently become interested in investigating how changes in microbiota landscape influence neurodevelopmental disorder pathogenesis. In this review, we highlight emerging data describing roles for microbiota in the development of autism-related behavioral abnormalities. These recent findings identify the immune system as a link between gut microbiota and the brain in neurodevelopmental disorders, and suggest that targeting the microbiome and maternal immune responses during gestation may offer strategies to limit autism development in at-risk pregnancies.


Assuntos
Transtorno do Espectro Autista/etiologia , Microbioma Gastrointestinal/imunologia , Sistema Imunitário/imunologia , Transtornos do Neurodesenvolvimento/etiologia , Complicações Infecciosas na Gravidez/etiologia , Animais , Transtorno do Espectro Autista/patologia , Feminino , Humanos , Transtornos do Neurodesenvolvimento/patologia , Gravidez , Complicações Infecciosas na Gravidez/patologia
5.
Int J Mol Sci ; 20(6)2019 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-30875831

RESUMO

For the past few years there has been an exponential increase in the use of animal models to confirm the pathogenicity of candidate disease-causing genetic variants found in patients. One such animal model is the zebrafish. Despite being a non-mammalian animal, the zebrafish model has proven its potential in recapitulating the phenotypes of many different human genetic disorders. This review will focus on recent advances in the modeling of neurodevelopmental disorders in zebrafish, covering aspects from early brain development to techniques used for modulating gene expression, as well as how to best characterize the resulting phenotypes. We also review other existing models of neurodevelopmental disorders, and the current efforts in developing and testing compounds with potential therapeutic value.


Assuntos
Transtornos do Neurodesenvolvimento/patologia , Peixe-Zebra , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Modelos Animais de Doenças , Predisposição Genética para Doença , Humanos , Transtornos do Neurodesenvolvimento/genética , Fenótipo
6.
Nat Commun ; 10(1): 707, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755602

RESUMO

Aminoacyl-tRNA synthetases (ARSs) function to transfer amino acids to cognate tRNA molecules, which are required for protein translation. To date, biallelic mutations in 31 ARS genes are known to cause recessive, early-onset severe multi-organ diseases. VARS encodes the only known valine cytoplasmic-localized aminoacyl-tRNA synthetase. Here, we report seven patients from five unrelated families with five different biallelic missense variants in VARS. Subjects present with a range of global developmental delay, epileptic encephalopathy and primary or progressive microcephaly. Longitudinal assessment demonstrates progressive cortical atrophy and white matter volume loss. Variants map to the VARS tRNA binding domain and adjacent to the anticodon domain, and disrupt highly conserved residues. Patient primary cells show intact VARS protein but reduced enzymatic activity, suggesting partial loss of function. The implication of VARS in pediatric neurodegeneration broadens the spectrum of human diseases due to mutations in tRNA synthetase genes.


Assuntos
Epilepsia/genética , Mutação , Valina-tRNA Ligase/genética , Alelos , Anticódon , Criança , Pré-Escolar , Progressão da Doença , Epilepsia/enzimologia , Epilepsia/patologia , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/genética , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Biossíntese de Proteínas , Domínios e Motivos de Interação entre Proteínas , RNA de Transferência/genética , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma
7.
Nat Commun ; 10(1): 708, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755616

RESUMO

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.


Assuntos
Encefalopatias/genética , Microcefalia/genética , Valina-tRNA Ligase/genética , Alelos , Animais , Encefalopatias/enzimologia , Encefalopatias/patologia , Linhagem Celular , Modelos Animais de Doenças , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/patologia , Feminino , Fibroblastos , Técnicas de Inativação de Genes , Predisposição Genética para Doença , Humanos , Mutação com Perda de Função , Masculino , Microcefalia/enzimologia , Microcefalia/patologia , Modelos Moleculares , Transtornos do Neurodesenvolvimento/enzimologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Linhagem , Prosencéfalo/patologia , Peixe-Zebra
8.
Dev Neuropsychol ; 44(2): 203-219, 2019 Mar-Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30661412

RESUMO

Oxygenated (HBO) and deoxygenated hemoglobin (HBR) levels in the prefrontal cortex (PFC) were measured using functional near-infrared spectroscopy (fNIRS) to determine if PFC activity during a cognitive inhibition task distinguishes children with prenatal alcohol exposure (PAE, n = 26) from both typically developing controls (n = 19) and a contrast group of children with other neurobehavioral problems (n = 14). Despite showing evidence of increased PFC activity in the non-inhibitory condition relative to controls, children in the PAE group displayed reduced PFC HBO and increased HBR relative to both other groups in the inhibitory condition, suggesting reduced PFC activity but increased oxygen consumption without sufficient oxygen replacement.


Assuntos
Transtornos do Espectro Alcoólico Fetal/diagnóstico , Transtornos do Neurodesenvolvimento/etiologia , Espectroscopia de Luz Próxima ao Infravermelho/métodos , Adolescente , Criança , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Humanos , Masculino , Transtornos do Neurodesenvolvimento/patologia , Gravidez
9.
Pediatr Diabetes ; 20(3): 345-352, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30652399

RESUMO

OBJECTIVE: Psychiatric diagnoses of patients with type 1 diabetes mellitus (T1DM), the severity of attention deficit/hyperactivity disorder (ADHD) symptoms of the patients and their primary caregivers, and the effects of these factors on treatment were investigated. METHODS: Sixty-one patients with T1DM were included in the study along with their parents. Psychiatric diagnoses of the patients were determined using a semistructured psychiatric interview, and their depression and ADHD symptom severities were evaluated with self-report scales. The ADHD symptom severities of the parents were evaluated using self-report scales. The relationships among the psychiatric symptoms and the hemoglobin A1c (HbA1c), fasting blood glucose (FBG), and postprandial blood glucose (PBG) levels of the patients were investigated. RESULTS: HbA1c levels were found to correlate with the hyperactivity levels of children and the number of diagnoses they had. FBG and PBG values of patients diagnosed with ADHD were found to be higher than in those who did not have ADHD. HbA1c, FBG, and PBG values of the patients who had any disruptive behavior disorder were found to be higher than in those who did not. ADHD total scores, gender (being female), having diagnoses of ADHD or depression were found to be predictive of HbA1c levels according to the regression analyses. No relationship between the clinical findings of the children and their parents' ADHD levels was found. CONCLUSIONS: The findings of this study implicate that children with T1DM should be evaluated in terms of ADHD which could have negative effects on the treatment.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/complicações , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/terapia , Transtornos do Neurodesenvolvimento/complicações , Adolescente , Idade de Início , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/patologia , Criança , Depressão/complicações , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/patologia , Diabetes Mellitus Tipo 1/epidemiologia , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/patologia , Pais/psicologia , Prognóstico , Autorrelato , Índice de Gravidade de Doença , Resultado do Tratamento
10.
Dev Biol ; 448(1): 36-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30695685

RESUMO

Joubert syndrome (JBTS) is a predominantly autosomal recessive neurodevelopmental disorder that presents with characteristic malformations of the cerebellar vermis, superior cerebellar peduncles and midbrain in humans. Accompanying these malformations are a heterogeneous set of clinical symptoms, which frequently include deficits in motor and muscle function, such as hypotonia (low muscle tone) and ataxia (clumsiness). These symptoms are attributed to improper development of the hindbrain, but no direct evidence has been reported linking these in JBTS. Here, we describe muscle developmental defects in a mouse with a targeted deletion of the Abelson helper integration site 1 gene, Ahi1, one of the genes known to cause JBTS in humans. While FVB/NJ Ahi1-/- mice display no gross malformations of the cerebellum, deficits are observed in several measures of motor function, strength, and body development. Specifically, Ahi1-/- mice show delayed physical development, delays in surface reflex righting as neonates, and reductions in grip strength and spontaneous locomotor activity as adults. Additionally, Ahi1-/- mice showed evidence of muscle-specific contributions to this phenotype, such as reductions in 1) myoblast differentiation potential in vitro, 2) muscle desmin expression, and 3) overall muscle mass, myonuclear domain, and muscle fiber cross-sectional area. Together, these data suggest that loss of Ahi1 may cause abnormalities in the differentiation of myoblasts to mature muscle cells. Moreover, Ahi1 loss impacts muscle development directly, outside of any indirect impact of cerebellar malformations, revealing a novel myogenic cause for hypotonia in JBTS.


Assuntos
Anormalidades Múltiplas/embriologia , Diferenciação Celular , Cerebelo/anormalidades , Anormalidades do Olho/embriologia , Doenças Renais Císticas/embriologia , Desenvolvimento Muscular , Transtornos do Neurodesenvolvimento/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Retina/anormalidades , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/patologia , Animais , Cerebelo/embriologia , Cerebelo/patologia , Desmina/genética , Desmina/metabolismo , Anormalidades do Olho/genética , Anormalidades do Olho/patologia , Doenças Renais Císticas/genética , Doenças Renais Císticas/patologia , Locomoção/genética , Camundongos , Camundongos Knockout , Força Muscular/genética , Mioblastos/metabolismo , Mioblastos/patologia , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/patologia , Proteínas Proto-Oncogênicas/metabolismo , Reflexo de Endireitamento/genética , Retina/embriologia , Retina/patologia
11.
J Hum Genet ; 64(4): 271-280, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30670789

RESUMO

A decade ago, we described novel de novo submicroscopic deletions of chromosome 14q11.2 in three children with developmental delay, cognitive impairment, and similar dysmorphic features, including widely-spaced eyes, short nose with flat nasal bridge, long philtrum, prominent Cupid's bow of the upper lip, full lower lip, and auricular anomalies. We suggested that this constituted a new multiple congenital anomaly-intellectual disability syndrome due to defects in CHD8 and/or SUPT16H. The three patients in our original cohort were between 2 years and 3 years of age at the time. Here we present a fourth patient and clinical updates on our previous patients. To document the longitudinal course more fully, we integrate published reports of other patients and describe genotype-phenotype correlations among them. Children with the disorder present with developmental delay, intellectual disability, and/or autism spectrum disorder in addition to characteristic facies. Gastrointestinal and sleep problems are notable. The identification of multiple patients with the same genetic defect and characteristic clinical phenotype, confirms our suggestion that this is a syndromic disorder caused by haploinsufficiency or heterozygous loss of function of CHD8.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Fatores de Transcrição/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/fisiopatologia , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/fisiopatologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 14/genética , Facies , Feminino , Haploinsuficiência/genética , Heterozigoto , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/genética , Megalencefalia/fisiopatologia , Transtornos do Neurodesenvolvimento/patologia
13.
J Neurodev Disord ; 10(1): 38, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30541449

RESUMO

BACKGROUND: Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and functional connectivity, with persistent changes evident across advanced magnetic resonance imaging modalities as early as the neonatal period. Emerging findings from cross-sectional and longitudinal investigations increasingly suggest that aberrant connectivity within key functional networks and white matter tracts may underlie the neurodevelopmental impairments common in this population. MAIN BODY: This review begins by highlighting the elevated rates of neurodevelopmental disorders across domains in this clinical population, describes the patterns of aberrant structural and functional connectivity common in prematurely-born infants and children, and then reviews the increasingly established body of literature delineating the relationship between these brain abnormalities and adverse neurodevelopmental outcomes. We also detail important, typically understudied, clinical, and social variables that may influence these relationships among preterm children, including heritability and psychosocial risks. CONCLUSION: Future work in this domain should continue to leverage longitudinal evaluations of preterm infants which include both neuroimaging and detailed serial neurodevelopmental assessments to further characterize relationships between imaging measures and impairment, information necessary for advancing our understanding of modifiable risk factors underlying these disorders and best practices for improving neurodevelopmental trajectories in this high-risk clinical population.


Assuntos
Encéfalo/patologia , Encéfalo/fisiopatologia , Recém-Nascido Prematuro/fisiologia , Transtornos do Neurodesenvolvimento/patologia , Transtornos do Neurodesenvolvimento/fisiopatologia , Mapeamento Encefálico , Humanos , Recém-Nascido , Recém-Nascido Prematuro/psicologia , Imagem por Ressonância Magnética , Vias Neurais/patologia , Vias Neurais/fisiopatologia
14.
Am J Hum Genet ; 103(6): 829-857, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526865

RESUMO

The analysis of animal models of neurological disease has been instrumental in furthering our understanding of neurodevelopment and brain diseases. However, animal models are limited in revealing some of the most fundamental aspects of development, genetics, pathology, and disease mechanisms that are unique to humans. These shortcomings are exaggerated in disorders that affect the brain, where the most significant differences between humans and animal models exist, and could underscore failures in targeted therapeutic interventions in affected individuals. Human pluripotent stem cells have emerged as a much-needed model system for investigating human-specific biology and disease mechanisms. However, questions remain regarding whether these cell-culture-based models are sufficient or even necessary. In this review, we summarize human-specific features of neurodevelopment and the most common neurodevelopmental disorders, present discrepancies between animal models and human diseases, demonstrate how human stem cell models can provide meaningful information, and discuss the challenges that exist in our pursuit to understand distinctively human aspects of neurodevelopment and brain disease. This information argues for a more thoughtful approach to disease modeling through consideration of the valuable features and limitations of each model system, be they human or animal, to mimic disease characteristics.


Assuntos
Transtornos do Neurodesenvolvimento/patologia , Animais , Encéfalo/patologia , Técnicas de Cultura de Células , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Biológicos
15.
Proc Natl Acad Sci U S A ; 115(41): E9717-E9726, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30242134

RESUMO

Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.


Assuntos
Variações do Número de Cópias de DNA , Glicoproteínas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/genética , Sinapses/fisiologia , Animais , Movimento Celular , Células Cultivadas , Endocitose , Glicoproteínas/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/patologia , Transporte Proteico , Proteólise , Células de Purkinje/metabolismo
16.
Handb Clin Neurol ; 154: 167-180, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29903438

RESUMO

The question posed today is not whether the cerebellum plays a role in cognition, but instead, how the cerebellum contributes to cognitive processes, even in the developmental age. The central role of the cerebellum in many areas of human abilities, motor as well as cognitive, in childhood as well as in adulthood, is well established but cerebellar basic functioning is still not clear and is much debated. Of particular interest is the changing face of cerebellar influence on motor, higher cognitive, and behavioral functioning when adult and developmental lesions are compared. The idea that the cerebellum might play quite different roles during development and in adulthood has been proposed, and evidence from experimental and clinical literature has been provided, including for sequencing, behavioral aspects, and executive functions Still, more data are needed to fully understand the changes of cerebrocerebellar interactions within the segregated loops which connect cerebrum and cerebellum, not only between childhood and adulthood but also in health and disease.


Assuntos
Cerebelo/fisiologia , Cognição/fisiologia , Função Executiva/fisiologia , Doenças Cerebelares/complicações , Cerebelo/patologia , Humanos , Transtornos do Neurodesenvolvimento/patologia
17.
J Vis Exp ; (133)2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29553565

RESUMO

Human brain development proceeds through a series of precisely orchestrated processes, with earlier stages distinguished by proliferation, migration, and neurite outgrowth; and later stages characterized by axon/dendrite outgrowth and synapse formation. In neurodevelopmental disorders, often one or more of these processes are disrupted, leading to abnormalities in brain formation and function. With the advent of human induced pluripotent stem cell (hiPSC) technology, researchers now have an abundant supply of human cells that can be differentiated into virtually any cell type, including neurons. These cells can be used to study both normal brain development and disease pathogenesis. A number of protocols using hiPSCs to model neuropsychiatric disease use terminally differentiated neurons or use 3D culture systems termed organoids. While these methods have proven invaluable in studying human disease pathogenesis, there are some drawbacks. Differentiation of hiPSCs into neurons and generation of organoids are lengthy and costly processes that can impact the number of experiments and variables that can be assessed. In addition, while post-mitotic neurons and organoids allow the study of disease-related processes, including dendrite outgrowth and synaptogenesis, they preclude the study of earlier processes like proliferation and migration. In neurodevelopmental disorders, such as autism, abundant genetic and post-mortem evidence indicates defects in early developmental processes. Neural precursor cells (NPCs), a highly proliferative cell population, may be a suitable model in which to ask questions about ontogenetic processes and disease initiation. We now extend methodologies learned from studying development in mouse and rat cortical cultures to human NPCs. The use of NPCs allows us to investigate disease-related phenotypes and define how different variables (e.g., growth factors, drugs) impact developmental processes including proliferation, migration, and differentiation in only a few days. Ultimately, this toolset can be used in a reproducible and high-throughput manner to identify disease-specific mechanisms and phenotypes in neurodevelopmental disorders.


Assuntos
Células-Tronco Neurais/metabolismo , Transtornos do Neurodesenvolvimento/diagnóstico , Neurônios/metabolismo , Animais , Diferenciação Celular , Movimento Celular , Humanos , Camundongos , Células-Tronco Neurais/citologia , Transtornos do Neurodesenvolvimento/patologia , Fenótipo , Ratos
18.
J Biochem ; 163(6): 447-455, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29415158

RESUMO

Synaptic connections are essential for neural circuits in order to convey brain functions. The postsynaptic density (PSD) is a huge protein complex associated with postsynaptic membranes of excitatory synapses. In mammals, the PSD is composed of more than 1,000 proteins including receptors, scaffold proteins, signalling enzymes and cytoskeletal proteins. PSD proteins are crucial for synaptic transmission and plasticity. Proteomic studies have revealed the composition of PSD proteins in various species, brain regions and specific physiological conditions. Abnormalities with PSD proteins are linked to various neuropsychiatric diseases including neurodevelopmental disorders such as autism spectrum disorder and schizophrenia. Here, we review different kinds of proteomic studies of the PSD and the involvement of PSD proteins in physiological and pathological conditions.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Animais , Humanos , Transtornos do Neurodesenvolvimento/patologia , Proteômica
19.
Proc Natl Acad Sci U S A ; 115(7): 1558-1563, 2018 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-29386386

RESUMO

RING1 is an E3-ubiquitin ligase that is involved in epigenetic control of transcription during development. It is a component of the polycomb repressive complex 1, and its role in that complex is to ubiquitylate histone H2A. In a 13-year-old girl with syndromic neurodevelopmental disabilities, we identified a de novo mutation, RING1 p.R95Q, which alters a conserved arginine residue in the catalytic RING domain. In vitro assays demonstrated that the mutant RING1 retains capacity to catalyze ubiquitin chain formation, but is defective in its ability to ubiquitylate histone H2A in nucleosomes. Consistent with this in vitro effect, cells of the patient showed decreased monoubiquitylation of histone H2A. We modeled the mutant RING1 in Caenorhabditis elegans by editing the comparable amino acid change into spat-3, the suggested RING1 ortholog. Animals with either the missense mutation or complete knockout of spat-3 were defective in monoubiquitylation of histone H2A and had defects in neuronal migration and axon guidance. Relevant to our patient, animals heterozygous for either the missense or knockout allele also showed neuronal defects. Our results support three conclusions: mutation of RING1 is the likely cause of a human neurodevelopmental syndrome, mutation of RING1 can disrupt histone H2A ubiquitylation without disrupting RING1 catalytic activity, and the comparable mutation in C. elegans spat-3 both recapitulates the effects on histone H2A ubiquitylation and leads to neurodevelopmental abnormalities. This role for RING1 adds to our understanding of the importance of aberrant epigenetic effects as causes of human neurodevelopmental disorders.


Assuntos
Caenorhabditis elegans/crescimento & desenvolvimento , Epigênese Genética , Regulação da Expressão Gênica no Desenvolvimento , Mutação , Transtornos do Neurodesenvolvimento/genética , Complexo Repressor Polycomb 1/genética , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Estudos de Casos e Controles , Histonas/genética , Histonas/metabolismo , Humanos , Transtornos do Neurodesenvolvimento/patologia , Nucleossomos/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitinação
20.
Psychopathology ; 51(2): 71-75, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29478063

RESUMO

Epigenetic modification, such as DNA methylation (DNAm), is a mechanism that can help explain how early adversities can engender long-term vulnerability for mental health problems. At present, there is preliminary evidence to support the possibility of epigenetic mediation: environmental factors are reported to influence offspring DNAm, which in turn associate with child and adolescent psychopathology. However, all analyses have been correlational in nature and, as these studies have focussed on children and adolescents, DNAm has been based on peripheral tissue (cord blood, whole blood, buccal cells). Therefore, the extent to which DNAm could represent a causal mechanism (e.g., a surrogate of central nervous system function) or a biomarker (i.e., an indicator of the pathological process leading to disease) is unclear. This short report has 2 main components. First, 2 studies are summarized, one a candidate gene study and the other an epigenome-wide association study in which DNAm was reported to (partially) mediate the link between adversity and child development. Second, there is a discussion of (1) the "tissue issue," (2) maximizing the interpretability of candidate gene and epigenome-wide approaches, and (3) the need for examining DNAm as a potential biomarker for mental health. It is argued that advances within these 3 areas will make clearer the role of DNAm in the link between adversity and child and adolescent mental health.


Assuntos
Epigênese Genética/genética , Epigenômica/métodos , Saúde Mental/normas , Transtornos do Neurodesenvolvimento/diagnóstico , Adolescente , Criança , Feminino , Humanos , Masculino , Mucosa Bucal , Transtornos do Neurodesenvolvimento/patologia
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