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1.
Int J Mol Sci ; 22(19)2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34639097

RESUMO

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with extensive genetic and aetiological heterogeneity. While the underlying molecular mechanisms involved remain unclear, significant progress has been facilitated by recent advances in high-throughput transcriptomic, epigenomic and proteomic technologies. Here, we review recently published ASD proteomic data and compare proteomic functional enrichment signatures with those of transcriptomic and epigenomic data. We identify canonical pathways that are consistently implicated in ASD molecular data and find an enrichment of pathways involved in mitochondrial metabolism and neurogenesis. We identify a subset of differentially expressed proteins that are supported by ASD transcriptomic and DNA methylation data. Furthermore, these differentially expressed proteins are enriched for disease phenotype pathways associated with ASD aetiology. These proteins converge on protein-protein interaction networks that regulate cell proliferation and differentiation, metabolism, and inflammation, which demonstrates a link between canonical pathways, biological processes and the ASD phenotype. This review highlights how proteomics can uncover potential molecular mechanisms to explain a link between mitochondrial dysfunction and neurodevelopmental pathology.


Assuntos
Transtorno do Espectro Autista/patologia , Metilação de DNA , Epigênese Genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Proteoma , Transcriptoma , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Humanos , Fenótipo , Mapas de Interação de Proteínas
2.
Transl Psychiatry ; 11(1): 527, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34645790

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is associated with unique changes in mitochondrial metabolism, including elevated respiration rates and morphological alterations. We examined electron transport chain (ETC) complex activity in fibroblasts derived from 18 children with ASD as well as mitochondrial morphology measurements in fibroblasts derived from the ASD participants and four typically developing controls. In ASD participants, symptoms severity was measured by the Social Responsiveness Scale and Aberrant Behavior Checklist. Mixed-model regression demonstrated that alterations in mitochondrial morphology were associated with both ETC Complex I+III and IV activity as well as the difference between ETC Complex I+III and IV activity. The subgroup of ASD participants with relative elevation in Complex IV activity demonstrated more typical mitochondrial morphology and milder ASD related symptoms. This study is limited by sample size given the invasive nature of obtaining fibroblasts from children. Furthermore, since mitochondrial function is heterogenous across tissues, the result may be specific to fibroblast respiration. Previous studies have separately described elevated ETC Complex IV activity and changes in mitochondrial morphology in cells derived from children with ASD but this is the first study to link these two findings in mitochondrial metabolism. The association between a difference in ETC complex I+III and IV activity and normal morphology suggests that mitochondrial in individuals with ASD may require ETC uncoupling to function optimally. Further studies should assess the molecular mechanisms behind these unique metabolic changes.Trial registration: Protocols used in this study were registered in clinicaltrials.gov as NCT02000284 and NCT02003170.


Assuntos
Transtorno do Espectro Autista , Transtorno do Espectro Autista/metabolismo , Transporte de Elétrons , Complexo I de Transporte de Elétrons , Humanos , Mitocôndrias/metabolismo , Oxirredução
3.
Nat Commun ; 12(1): 6084, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34667149

RESUMO

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism spectrum disorder (ASD), with a putative link to aberrant mTOR-dependent synaptic pruning. ASD is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses causes aberrant functional connectivity in ASD. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with ASD -like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic ASD exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for ASD-dysregulated genes interacting with mTOR or Tsc2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism.


Assuntos
Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/fisiopatologia , Sinapses/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adolescente , Animais , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Córtex Cerebral/fisiopatologia , Criança , Feminino , Haploinsuficiência , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sinapses/genética , Serina-Treonina Quinases TOR/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
4.
Nat Commun ; 12(1): 4087, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471112

RESUMO

We utilized forebrain organoids generated from induced pluripotent stem cells of patients with a syndromic form of Autism Spectrum Disorder (ASD) with a homozygous protein-truncating mutation in CNTNAP2, to study its effects on embryonic cortical development. Patients with this mutation present with clinical characteristics of brain overgrowth. Patient-derived forebrain organoids displayed an increase in volume and total cell number that is driven by increased neural progenitor proliferation. Single-cell RNA sequencing revealed PFC-excitatory neurons to be the key cell types expressing CNTNAP2. Gene ontology analysis of differentially expressed genes (DEgenes) corroborates aberrant cellular proliferation. Moreover, the DEgenes are enriched for ASD-associated genes. The cell-type-specific signature genes of the CNTNAP2-expressing neurons are associated with clinical phenotypes previously described in patients. The organoid overgrowth phenotypes were largely rescued after correction of the mutation using CRISPR-Cas9. This CNTNAP2-organoid model provides opportunity for further mechanistic inquiry and development of new therapeutic strategies for ASD.


Assuntos
Transtorno do Espectro Autista/metabolismo , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Organoides/metabolismo , Prosencéfalo/metabolismo , Adolescente , Transtorno do Espectro Autista/genética , Diferenciação Celular , Proliferação de Células , Criança , Feminino , Predisposição Genética para Doença/genética , Humanos , Células-Tronco Pluripotentes Induzidas , Proteínas de Membrana/genética , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Fenótipo , Análise de Sequência de RNA
5.
Sci Rep ; 11(1): 17825, 2021 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-34497307

RESUMO

Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.


Assuntos
Transtorno do Espectro Autista/genética , Diferenciação Celular/genética , Microglia/metabolismo , Oligodendroglia/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Expressão Gênica , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Oligodendroglia/citologia , Oligodendroglia/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Fagocitose/genética , Proteína 2 do Complexo Esclerose Tuberosa/genética , Proteína 2 do Complexo Esclerose Tuberosa/metabolismo
6.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576185

RESUMO

Although it has been over 20 years since Neural Cell Adhesion Molecule 2 (NCAM2) was identified as the second member of the NCAM family with a high expression in the nervous system, the knowledge of NCAM2 is still eclipsed by NCAM1. The first studies with NCAM2 focused on the olfactory bulb, where this protein has a key role in axonal projection and axonal/dendritic compartmentalization. In contrast to NCAM1, NCAM2's functions and partners in the brain during development and adulthood have remained largely unknown until not long ago. Recent studies have revealed the importance of NCAM2 in nervous system development. NCAM2 governs neuronal morphogenesis and axodendritic architecture, and controls important neuron-specific processes such as neuronal differentiation, synaptogenesis and memory formation. In the adult brain, NCAM2 is highly expressed in dendritic spines, and it regulates synaptic plasticity and learning processes. NCAM2's functions are related to its ability to adapt to the external inputs of the cell and to modify the cytoskeleton accordingly. Different studies show that NCAM2 interacts with proteins involved in cytoskeleton stability and proteins that regulate calcium influx, which could also modify the cytoskeleton. In this review, we examine the evidence that points to NCAM2 as a crucial cytoskeleton regulation protein during brain development and adulthood. This key function of NCAM2 may offer promising new therapeutic approaches for the treatment of neurodevelopmental diseases and neurodegenerative disorders.


Assuntos
Doença de Alzheimer/metabolismo , Transtorno do Espectro Autista/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Actinas/genética , Actinas/metabolismo , Doença de Alzheimer/genética , Animais , Transtorno do Espectro Autista/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Humanos , Microtúbulos/genética , Microtúbulos/metabolismo , Moléculas de Adesão de Célula Nervosa/genética
7.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502168

RESUMO

Autism spectrum disorder (ASD) is an umbrella term that includes many different disorders that affect the development, communication, and behavior of an individual. Prevalence of ASD has risen exponentially in the past couple of decades. ASD has a complex etiology and traditionally recognized risk factors only account for a small percentage of incidence of the disorder. Recent studies have examined factors beyond the conventional risk factors (e.g., environmental pollution). There has been an increase in air pollution since the beginning of industrialization. Most environmental pollutants cause toxicities through activation of several cellular receptors, such as the aryl hydrocarbon receptor (AhR)/cytochrome P450 (CYPs) pathway. There is little research on the involvement of AhR in contributing to ASD. Although a few reviews have discussed and addressed the link between increased prevalence of ASD and exposure to environmental pollutants, the mechanism governing this effect, specifically the role of AhR in ASD development and the molecular mechanisms involved, have not been discussed or reviewed before. This article reviews the state of knowledge regarding the impact of the AhR/CYP pathway modulation upon exposure to environmental pollutants on ASD risk, incidence, and development. It also explores the molecular mechanisms involved, such as epigenesis and polymorphism. In addition, the review explores possible new AhR-mediated mechanisms of several drugs used for treatment of ASD, such as sulforaphane, resveratrol, haloperidol, and metformin.


Assuntos
Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/metabolismo , Suscetibilidade a Doenças , Poluentes Ambientais/efeitos adversos , Receptores de Hidrocarboneto Arílico/metabolismo , Poluição do Ar/efeitos adversos , Animais , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Biomarcadores , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Modelos Animais de Doenças , Exposição Ambiental/efeitos adversos , Poluição Ambiental/efeitos adversos , Epigênese Genética , Regulação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Transdução de Sinais
8.
Biomolecules ; 11(8)2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34439901

RESUMO

Because of their abilities to catalyze generation of toxic free radical species, free concentrations of the redox reactive metals iron and copper are highly regulated. Importantly, desired neurobiological effects of these redox reactive metal cations occur within very narrow ranges of their local concentrations. For example, synaptic release of free copper acts locally to modulate NMDA receptor-mediated neurotransmission. Moreover, within the developing brain, iron is critical to hippocampal maturation and the differentiation of parvalbumin-expressing neurons, whose soma and dendrites are surrounded by perineuronal nets (PNNs). The PNNs are a specialized component of brain extracellular matrix, whose polyanionic character supports the fast-spiking electrophysiological properties of these parvalbumin-expressing GABAergic interneurons. In addition to binding cations and creation of the Donnan equilibrium that support the fast-spiking properties of this subset of interneurons, the complex architecture of PNNs also binds metal cations, which may serve a protective function against oxidative damage, especially of these fast-spiking neurons. Data suggest that pathological disturbance of the population of fast-spiking, parvalbumin-expressing GABAergic inhibitory interneurons occur in at least some clinical presentations, which leads to disruption of the synchronous oscillatory output of assemblies of pyramidal neurons. Increased expression of the GluN2A NMDA receptor subunit on parvalbumin-expressing interneurons is linked to functional maturation of both these neurons and the perineuronal nets that surround them. Disruption of GluN2A expression shows increased susceptibility to oxidative stress, reflected in redox dysregulation and delayed maturation of PNNs. This may be especially relevant to neurodevelopmental disorders, including autism spectrum disorder. Conceivably, binding of metal redox reactive cations by the perineuronal net helps to maintain safe local concentrations, and also serves as a reservoir buffering against second-to-second fluctuations in their concentrations outside of a narrow physiological range.


Assuntos
Cátions , Metais/química , Transtornos do Neurodesenvolvimento/metabolismo , Animais , Transtorno do Espectro Autista/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Cobre/química , Matriz Extracelular/metabolismo , Homeostase , Humanos , Interneurônios/metabolismo , Íons , Ferro/química , Camundongos , Neurônios/metabolismo , Oscilometria , Oxirredução , Estresse Oxidativo , Parvalbuminas/metabolismo , Fosfolipídeos/química , Células Piramidais/citologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica
9.
Sci Rep ; 11(1): 15974, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354148

RESUMO

Difficulties with visual perspective-taking among individuals with autism spectrum disorders remain poorly understood. Many studies have presumed that first-person visual input can be mentally transformed to a third-person perspective during visual perspective-taking tasks; however, existing research has not fully revealed the computational strategy used by those with autism spectrum disorders for taking another person's perspective. In this study, we designed a novel approach to test a strategy using the opposite-directional effect among children with autism spectrum disorders. This effect refers to how a third-person perspective as a visual input alters a cognitive process. We directly manipulated participants' visual perspective by placing a camera at different positions; participants could watch themselves from a third-person perspective during a reaching task with no endpoint feedback. During a baseline task, endpoint bias (with endpoint feedback but no visual transformation) did not differ significantly between groups. However, the endpoint was affected by extrinsic coordinate information in the control group relative to the autism spectrum disorders group when the visual perspective was transformed. These results indicate an increased reliance on proprioception during the reaching task with perspective manipulation in the autism spectrum disorders group.


Assuntos
Transtorno do Espectro Autista/fisiopatologia , Retroalimentação Sensorial/fisiologia , Navegação Espacial/fisiologia , Adolescente , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/psicologia , Criança , Cognição , Feminino , Humanos , Masculino , Propriocepção , Percepção Visual/fisiologia
10.
Sci Rep ; 11(1): 15867, 2021 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-34354167

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by significant and complex genetic etiology. GWAS studies have identified genetic variants associated with ASD, but the functional impacts of these variants remain unknown. Here, we integrated four distinct levels of biological information (GWAS, eQTL, spatial genome organization and protein-protein interactions) to identify potential regulatory impacts of ASD-associated SNPs (p < 5 × 10-8) on biological pathways within fetal and adult cortical tissues. We found 80 and 58 SNPs that mark regulatory regions (i.e. expression quantitative trait loci or eQTLs) in the fetal and adult cortex, respectively. These eQTLs were also linked to other psychiatric disorders (e.g. schizophrenia, ADHD, bipolar disorder). Functional annotation of ASD-associated eQTLs revealed that they are involved in diverse regulatory processes. In particular, we found significant enrichment of eQTLs within regions repressed by Polycomb proteins in the fetal cortex compared to the adult cortex. Furthermore, we constructed fetal and adult cortex-specific protein-protein interaction networks and identified that ASD-associated regulatory SNPs impact on immune pathways, fatty acid metabolism, ribosome biogenesis, aminoacyl-tRNA biosynthesis and spliceosome in the fetal cortex. By contrast, in the adult cortex they largely affect immune pathways. Overall, our findings highlight potential regulatory mechanisms and pathways important for the etiology of ASD in early brain development and adulthood. This approach, in combination with clinical studies on ASD, will contribute to individualized mechanistic understanding of ASD development.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Córtex Cerebral/metabolismo , Adulto , Encéfalo/fisiopatologia , Bases de Dados Genéticas , Feto , Redes Reguladoras de Genes/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Transtornos do Neurodesenvolvimento/genética , Polimorfismo de Nucleotídeo Único/genética , Mapeamento de Interação de Proteínas/métodos , Locos de Características Quantitativas/genética
11.
Cells ; 10(8)2021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34440744

RESUMO

Folic acid has been identified to be integral in rapid tissue growth and cell division during fetal development. Different studies indicate folic acid's importance in improving childhood behavioral outcomes and underline its role as a modifiable risk factor for autism spectrum disorders. The aim of this systematic review is to both elucidate the potential role of folic acid in autism spectrum disorders and to investigate the mechanisms involved. Studies have pointed out a potential beneficial effect of prenatal folic acid maternal supplementation (600 µg) on the risk of autism spectrum disorder onset, but opposite results have been reported as well. Folic acid and/or folinic acid supplementation in autism spectrum disorder diagnosed children has led to improvements, both in some neurologic and behavioral symptoms and in the concentration of one-carbon metabolites. Several authors report an increased frequency of serum auto-antibodies against folate receptor alpha (FRAA) in autism spectrum disorder children. Furthermore, methylene tetrahydrofolate reductase (MTHFR) polymorphisms showed a significant influence on ASD risk. More clinical trials, with a clear study design, with larger sample sizes and longer observation periods are necessary to be carried out to better evaluate the potential protective role of folic acid in autism spectrum disorder risk.


Assuntos
Transtorno do Espectro Autista/patologia , Ácido Fólico/metabolismo , Transtorno do Espectro Autista/metabolismo , Autoanticorpos/sangue , Suplementos Nutricionais , Receptor 1 de Folato/imunologia , Ácido Fólico/administração & dosagem , Humanos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Fatores de Risco
12.
J Neurosci ; 41(37): 7768-7778, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34353896

RESUMO

We recently identified an autism spectrum disorder/intellectual disability (ASD/ID)-related de novo mutation hotspot in the Rac1-activating GEF1 domain of the protein Trio. Trio is a Rho guanine nucleotide exchange factor (RhoGEF) that is essential for glutamatergic synapse function. An ASD/ID-related mutation identified in Trio's GEF1 domain, Trio D1368V, produces a pathologic increase in glutamatergic synaptogenesis, suggesting that Trio is coupled to synaptic regulatory mechanisms that govern glutamatergic synapse formation. However, the molecular mechanisms by which Trio regulates glutamatergic synapses are largely unexplored. Here, using biochemical methods, we identify an interaction between Trio and the synaptogenic protein Neuroligin 1 (NLGN1) in the brain. Molecular biological approaches were then combined with super-resolution dendritic spine imaging and whole-cell voltage-clamp electrophysiology in hippocampal slices from male and female rats to examine the impact ASD/ID-related Trio mutations have on NLGN1-mediated synaptogenesis. We find that an ASD/ID-related mutation in Trio's eighth spectrin repeat region, Trio N1080I, inhibits Trio's interaction with NLGN1 and prevents Trio D1368V-mediated synaptogenesis. Inhibiting Trio's interaction with NLGN1 via Trio N1080I blocked NLGN1-mediated synaptogenesis and increases in synaptic NMDA Receptor function but not NLGN1-mediated increases in synaptic AMPA Receptor function. Finally, we show that the aberrant synaptogenesis produced by Trio D1368V is dependent on NLGN signaling. Our findings demonstrate that ASD/ID-related mutations in Trio are able to pathologically increase as well as decrease NLGN-mediated effects on glutamatergic neurotransmission, and point to an NLGN1-Trio interaction as part of a key pathway involved in ASD/ID etiology.SIGNIFICANCE STATEMENT A number of genes have been implicated in the development of autism spectrum disorder/intellectual disability (ASD/ID) in humans. It is now important to identify relationships between these genes to uncover specific cellular regulatory pathways that contribute to these disorders. In this study, we discover that two glutamatergic synapse regulatory proteins implicated in ASD/ID, Trio and Neuroligin 1, interact with one another to promote glutamatergic synaptogenesis. We also identify ASD/ID-related mutations in Trio that either inhibit or augment Neuroligin 1-mediated glutamatergic synapse formation. Together, our results identify a synaptic regulatory pathway that, when disrupted, likely contributes to the development of ASD/ID. Going forward, it will be important to determine whether this pathway represents a point of convergence of other proteins implicated in ASD/ID.


Assuntos
Transtorno do Espectro Autista/genética , Moléculas de Adesão Celular Neuronais/genética , Deficiência Intelectual/genética , Mutação , Sinapses/genética , Animais , Transtorno do Espectro Autista/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Espinhas Dendríticas/genética , Espinhas Dendríticas/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Hipocampo/metabolismo , Deficiência Intelectual/metabolismo , Masculino , Neurogênese/fisiologia , Ratos , Ratos Sprague-Dawley , Sinapses/metabolismo
13.
Int J Mol Sci ; 22(14)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34298871

RESUMO

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.


Assuntos
Transtorno do Espectro Autista/tratamento farmacológico , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/tratamento farmacológico , Curcumina/farmacologia , Hipocampo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Transtorno Autístico/metabolismo , Colina/farmacologia , Modelos Animais de Doenças , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Agonistas Nicotínicos/farmacologia , Comportamento Social
14.
Nat Commun ; 12(1): 4056, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210967

RESUMO

Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/patologia , Comportamento Animal/fisiologia , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Trissomia/genética , Animais , Transtorno do Espectro Autista/metabolismo , Cromossomos Humanos Par 15/genética , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Fenótipo
15.
Nat Commun ; 12(1): 4284, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34257281

RESUMO

The translocase of the outer mitochondrial membrane TOM constitutes the organellar entry gate for nearly all precursor proteins synthesized on cytosolic ribosomes. Thus, TOM presents the ideal target to adjust the mitochondrial proteome upon changing cellular demands. Here, we identify that the import receptor TOM70 is targeted by the kinase DYRK1A and that this modification plays a critical role in the activation of the carrier import pathway. Phosphorylation of TOM70Ser91 by DYRK1A stimulates interaction of TOM70 with the core TOM translocase. This enables transfer of receptor-bound precursors to the translocation pore and initiates their import. Consequently, loss of TOM70Ser91 phosphorylation results in a strong decrease in import capacity of metabolite carriers. Inhibition of DYRK1A impairs mitochondrial structure and function and elicits a protective transcriptional response to maintain a functional import machinery. The DYRK1A-TOM70 axis will enable insights into disease mechanisms caused by dysfunctional DYRK1A, including autism spectrum disorder, microcephaly and Down syndrome.


Assuntos
Transtorno do Espectro Autista/metabolismo , Mitocôndrias/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Transtorno do Espectro Autista/genética , Citosol/metabolismo , Síndrome de Down/genética , Síndrome de Down/metabolismo , Humanos , Microcefalia/genética , Microcefalia/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial/genética , Fosforilação , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética
16.
Int J Mol Sci ; 22(14)2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-34299197

RESUMO

In recent years, accumulating evidence has shown that the innate immune complement system is involved in several aspects of normal brain development and in neurodevelopmental disorders, including autism spectrum disorder (ASD). Although abnormal expression of complement components was observed in post-mortem brain samples from individuals with ASD, little is known about the expression patterns of complement molecules in distinct cell types in the developing autistic brain. In the present study, we characterized the mRNA and protein expression profiles of a wide range of complement system components, receptors and regulators in induced pluripotent stem cell (iPSC)-derived neural progenitor cells, neurons and astrocytes of individuals with ASD and neurotypical controls, which constitute in vitro cellular models that recapitulate certain features of both human brain development and ASD pathophysiology. We observed that all the analyzed cell lines constitutively express several key complement molecules. Interestingly, using different quantification strategies, we found that complement C4 mRNA and protein are expressed in significantly lower levels by astrocytes derived from ASD individuals compared to control astrocytes. As astrocytes participate in synapse elimination, and diminished C4 levels have been linked to defective synaptic pruning, our findings may contribute to an increased understanding of the atypically enhanced brain connectivity in ASD.


Assuntos
Astrócitos/patologia , Transtorno do Espectro Autista/patologia , Complemento C4/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Células-Tronco Neurais/patologia , Neurônios/patologia , Astrócitos/metabolismo , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Células Cultivadas , Complemento C4/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Neurais/metabolismo , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo
17.
J Neurochem ; 159(1): 12-14, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34252196

RESUMO

Various neuroimaging approaches have reported alterations in brain connectivity in patients with autism spectrum disorder (ASD). Nevertheless, specific cellular and molecular mechanisms underlying these alterations remain to be elucidated. In the present Editorial, we highlight an article in the current issue of the Journal of Neurochemistry that provides first evidence for the structural and cellular basis of an atypical corpus callosum long-distance connectivity impairments observed in ASD patients. The authors used a juvenile valproic acid (VPA) rat model of ASD that presents with reduced myelin level, specifically in the corpus callosum, and with an altered myelin sheet structure that is closely associated with the behavioral alteration found in these rats. This hypomyelination occurs primarily during infancy prior to oligodendroglial alterations, implicating that axonal-oligodendroglial connections are compromised in this model. Concomitant with the hypomyelination, the ASD rat model showed an atypical brain metabolic pattern, with hypometabolic activity across the whole brain, and hypermetabolism in brain areas related to autistic-like behavior. These findings contribute to unravel the neurobiological basis underlying white matter alteration and altered long-distance brain connectivity as described in ASD, paving the way to the development of new early diagnostic markers and toward developing future specific therapies for ASD.


Assuntos
Transtorno Autístico/induzido quimicamente , Transtorno Autístico/metabolismo , Corpo Caloso/metabolismo , Rede Nervosa/metabolismo , Ácido Valproico/toxicidade , Animais , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/patologia , Transtorno Autístico/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Corpo Caloso/efeitos dos fármacos , Humanos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/patologia , Ratos
19.
Nat Neurosci ; 24(9): 1243-1255, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34253921

RESUMO

Despite a growing understanding of the molecular and developmental basis of autism spectrum disorder (ASD), how the neuronal encoding of social information is disrupted in ASD and whether it contributes to abnormal social behavior remains unclear. Here, we disrupted and then restored expression of the ASD-associated gene Shank3 in adult male mice while tracking the encoding dynamics of neurons in the medial prefrontal cortex (mPFC) over weeks. We find that Shank3 disruption led to a reduction of neurons encoding the experience of other mice and an increase in neurons encoding the animal's own experience. This shift was associated with a loss of ability by neurons to distinguish other from self and, therefore, the inability to encode social agency. Restoration of Shank3 expression in the mPFC reversed this encoding imbalance and increased sociability over 5-8 weeks. These findings reveal a neuronal-encoding process that is necessary for social behavior and that may be disrupted in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Proteínas dos Microfilamentos/genética , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Córtex Pré-Frontal/metabolismo , Comportamento Social , Animais , Transtorno do Espectro Autista/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Commun Biol ; 4(1): 756, 2021 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-34145365

RESUMO

Autism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.


Assuntos
Transtorno do Espectro Autista/genética , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Proteínas de Ligação a DNA/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Animais , Transtorno do Espectro Autista/metabolismo , Modelos Animais de Doenças , Desenvolvimento Embrionário/genética , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
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