RESUMEN
Methionine sulfoxide reductase A (MsrA) is an antioxidant enzyme that repairs the oxidation of methionine residues in proteins and free methionine in autism spectrum disorder (ASD). The present study aimed to assess the level of MsrA and neurotransmission enzymes in ASD individuals. Results confirmed that ASD associated with significant (P<0.05) reduction of MsrA and modulated mission enzymes. The role of MsrA as repair enzyme should be taken into account for study the activity of brain enzymes and proteins in ASD including ASMT that has a role in melatonin problems production in ASD due to higher AANAT level. The influence of MsrA also should be studied with MAT in mice to give more evidence.
Asunto(s)
Trastorno del Espectro Autista , Metionina Sulfóxido Reductasas , Humanos , Trastorno del Espectro Autista/enzimología , Metionina Sulfóxido Reductasas/metabolismo , Metionina Sulfóxido Reductasas/genética , Masculino , Femenino , Transmisión Sináptica , Niño , Melatonina/metabolismo , Adolescente , Preescolar , Adulto , Estudios de Casos y Controles , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/metabolismo , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genéticaRESUMEN
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in Drosophila neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.
Asunto(s)
Síndrome de Angelman , Trastorno del Espectro Autista , Proteínas de Drosophila , Drosophila melanogaster , Transmisión Sináptica , Ubiquitina-Proteína Ligasas , Animales , Síndrome de Angelman/enzimología , Síndrome de Angelman/genética , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/genética , Regulación hacia Abajo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Sinapsis/enzimología , Sinapsis/genéticaRESUMEN
Autism spectrum disorder is a pervasive neurodevelopmental disorder with a substantial contribution to the global disease burden. Despite intensive research efforts, the aetiopathogenesis remains unclear. The Janus-faced antioxidant enzymes superoxide dismutase 1-3 have been implicated in initiating oxidative stress and as such may constitute a potential therapeutic target. However, no measurement has been taken in human autistic brain samples. The aim of this study is to measure superoxide dismutase 1-3 in autistic cerebral organoids as an in vitro model of human foetal neurodevelopment. Whole brain organoids were created from induced pluripotent stem cells from healthy individuals (n = 5) and individuals suffering from autism (n = 4). Using Pierce bicinchoninic acid and enzyme-linked immunosorbent assays, the protein and superoxide dismutase 1, 2, and 3 concentrations were quantified in the cerebral organoids at days 22, 32, and 42. Measurements were normalized to the protein concentration. Results represented using medians and interquartile ranges. Using Wilcoxon matched-pairs signed-rank test, an abrupt rise in the superoxide dismutase concentration was observed at day 32 and onwards. Using Wilcoxon rank-sum test, no differences were observed between healthy (SOD1: 35.56 ng/mL ± 3.46; SOD2: 2435.80 ng/mL ± 1327.00; SOD3: 1854.88 ng/mL ± 867.94) and autistic (SOD1: 32.85 ng/mL ± 5.26; SOD2: 2717.80 ng/mL ± 1889.10; SOD3: 1690.18 ng/mL ± 615.49) organoids. Cerebral organoids recapitulate many aspects of human neurodevelopment, but the diffusion restriction may render efforts in modelling differences in oxidative stress futile due to the intrinsic hypoxia and central necrosis.
Asunto(s)
Trastorno del Espectro Autista , Organoides , Superóxido Dismutasa-1 , Superóxido Dismutasa , Trastorno del Espectro Autista/enzimología , Humanos , Isoenzimas , Organoides/enzimología , Estrés Oxidativo , Superóxido Dismutasa/metabolismo , Superóxido Dismutasa-1/metabolismoRESUMEN
Phosphatase and tensin homolog (PTEN) is a major negative regulator of the phosphatidylinositol-3-kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway. Loss-of-function mutations in PTEN have been found in a subset of patients with macrocephaly and autism spectrum disorder (ASD). PTEN loss in neurons leads to somal hypertrophy, aberrant migration, dendritic overgrowth, increased spine density, and hyperactivity of neuronal circuits. These neuronal overgrowth phenotypes are present on Pten knock-out (KO) and reconstitution with autism-associated point mutations. The mechanism underlying dendritic overgrowth in Pten deficient neurons is unclear. In this study, we examined how Pten loss impacts microtubule (MT) dynamics in both sexes using retroviral infection and transfection strategies to manipulate PTEN expression and tag the plus-end MT binding protein, end-binding protein 3 (EB3). We found Pten KO neurons sprout more new processes over time compared with wild-type (WT) neurons. We also found an increase in MT polymerization rate in Pten KO dendritic growth cones. Reducing MT polymerization rate to the WT level was sufficient to reduce dendritic overgrowth in Pten KO neurons in vitro and in vivo Finally, we found that rescue of dendritic overgrowth via inhibition of MT polymerization was sufficient to improve the performance of Pten KO mice in a spatial memory task. Taken together, our data suggests that one factor underlying PTEN loss dependent dendritic overgrowth is increased MT polymerization. This opens the possibility for an intersectional approach targeting MT polymerization and mTOR with low doses of inhibitors to achieve therapeutic gains with minimal side effects in pathologies associated with loss of neuronal PTEN function.SIGNIFICANCE STATEMENT Loss of Pten function because of genetic deletion or expression of mutations associated with autism spectrum disorder (ASD), results in overgrowth of neurons including increased total dendritic length and branching. We have discovered that this overgrowth is accompanied by increased rate of microtubule (MT) polymerization. The increased polymerization rate is insensitive to acute inhibition of mechanistic target of rapamycin (mTOR)C1 or protein synthesis. Direct pharmacological inhibition of MT polymerization can slow the polymerization rate in Pten knock-out (KO) neurons to rates seen in wild-type (WT) neurons. Correction of the MT polymerization rate rescues increased total dendritic arborization and spatial memory. Our studies suggest that phosphatase and tensin homolog (PTEN) inhibits dendritic growth through parallel regulation of protein synthesis and cytoskeletal polymerization.
Asunto(s)
Trastorno del Espectro Autista , Encéfalo , Microtúbulos , Fosfohidrolasa PTEN , Animales , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Encéfalo/citología , Encéfalo/enzimología , Encéfalo/metabolismo , Femenino , Humanos , Masculino , Ratones , Microtúbulos/metabolismo , Plasticidad Neuronal/fisiología , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Polimerizacion , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismoRESUMEN
Ongoing inchworm-like CAG and CGG repeat expansions in brains, arising by aberrant processing of slipped DNAs, may drive Huntington's disease, fragile X syndrome, and autism. FAN1 nuclease modifies hyper-expansion rates by unknown means. We show that FAN1, through iterative cycles, binds, dimerizes, and cleaves slipped DNAs, yielding striking exo-nuclease pauses along slip-outs: 5'-C↓A↓GC↓A↓G-3' and 5'-C↓T↓G↓C↓T↓G-3'. CAG excision is slower than CTG and requires intra-strand A·A and T·T mismatches. Fully paired hairpins arrested excision, whereas disease-delaying CAA interruptions further slowed excision. Endo-nucleolytic cleavage is insensitive to slip-outs. Rare FAN1 variants are found in individuals with autism with CGG/CCG expansions, and CGG/CCG slip-outs show exo-nuclease pauses. The slip-out-specific ligand, naphthyridine-azaquinolone, which induces contractions of expanded repeats in vivo, requires FAN1 for its effect, and protects slip-outs from FAN1 exo-, but not endo-, nucleolytic digestion. FAN1's inchworm pausing of slip-out excision rates is well suited to modify inchworm expansion rates, which modify disease onset and progression.
Asunto(s)
Trastorno del Espectro Autista/genética , Reparación de la Incompatibilidad de ADN , Endodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/metabolismo , Inestabilidad Genómica , Enfermedad de Huntington/genética , Enzimas Multifuncionales/metabolismo , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido , Animales , Trastorno del Espectro Autista/enzimología , Línea Celular Tumoral , Progresión de la Enfermedad , Endodesoxirribonucleasas/genética , Exodesoxirribonucleasas/genética , Predisposición Genética a la Enfermedad , Humanos , Enfermedad de Huntington/enzimología , Enzimas Multifuncionales/genética , Mutación , Conformación de Ácido Nucleico , Fenotipo , Unión Proteica , Células Sf9 , Ataxias Espinocerebelosas/enzimologíaRESUMEN
Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disorder, causing defects of social interaction and repetitive behaviors. Here, we identify a de novo heterozygous gene-truncating mutation of the Sentrin-specific peptidase1 (SENP1) gene in people with ASD without neurodevelopmental delay. We find that Senp1+/- mice exhibit core autistic-like symptoms such as social deficits and repetitive behaviors but normal learning and memory ability. Moreover, we find that inhibitory and excitatory synaptic functions are severely affected in the retrosplenial agranular (RSA) cortex of Senp1+/- mice. Lack of Senp1 leads to increased SUMOylation and degradation of fragile X mental retardation protein (FMRP), also implicated in syndromic ASD. Importantly, re-introducing SENP1 or FMRP specifically in RSA fully rescues the defects of synaptic function and autistic-like symptoms of Senp1+/- mice. Together, these results demonstrate that disruption of the SENP1-FMRP regulatory axis in the RSA causes autistic symptoms, providing a candidate region for ASD pathophysiology.
Asunto(s)
Trastorno del Espectro Autista/enzimología , Conducta Animal , Cisteína Endopeptidasas/metabolismo , Giro del Cíngulo/enzimología , Sinapsis/enzimología , Animales , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Trastorno del Espectro Autista/psicología , Estudios de Casos y Controles , Células Cultivadas , Cisteína Endopeptidasas/genética , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores , Femenino , Proteína de la Discapacidad Intelectual del Síndrome del Cromosoma X Frágil/metabolismo , Predisposición Genética a la Enfermedad , Aseo Animal , Giro del Cíngulo/fisiopatología , Haploinsuficiencia , Humanos , Potenciales Postsinápticos Inhibidores , Locomoción , Masculino , Aprendizaje por Laberinto , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación , Fenotipo , Conducta Social , SumoilaciónRESUMEN
Autism spectrum disorder (ASD) is a complex and multifactorial neurodevelopmental disorder characterized by the presence of restricted interests and repetitive behaviors besides deficits in social communication. Syndromic ASD is a subset of ASD caused by underlying genetic disorders, most commonly Fragile X Syndrome (FXS) and Rett Syndrome (RTT). Various mutations and consequent malfunctions in core signaling pathways have been identified in ASD, including glycogen synthase kinase 3 (GSK3). A growing body of evidence suggests a key role of GSK3 dysregulation in the pathogenesis of ASD and its related disorders. Here, we provide a synopsis of the implication of GSK3 in ASD, FXS, and RTT as a promising therapeutic target for the treatment of ASD.
Asunto(s)
Trastorno del Espectro Autista/tratamiento farmacológico , Trastorno del Espectro Autista/enzimología , Glucógeno Sintasa Quinasa 3/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/fisiopatología , Humanos , Transducción de Señal , Sinapsis/patología , Transmisión Sináptica , SíndromeRESUMEN
The Rho family GTPases are small G proteins that act as molecular switches shuttling between active and inactive forms. Rho GTPases are regulated by two classes of regulatory proteins, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Rho GTPases transduce the upstream signals to downstream effectors, thus regulating diverse cellular processes, such as growth, migration, adhesion, and differentiation. In particular, Rho GTPases play essential roles in regulating neuronal morphology and function. Recent evidence suggests that dysfunction of Rho GTPase signaling contributes substantially to the pathogenesis of autism spectrum disorder (ASD). It has been found that 20 genes encoding Rho GTPase regulators and effectors are listed as ASD risk genes by Simons foundation autism research initiative (SFARI). This review summarizes the clinical evidence, protein structure, and protein expression pattern of these 20 genes. Moreover, ASD-related behavioral phenotypes in animal models of these genes are reviewed, and the therapeutic approaches that show successful treatment effects in these animal models are discussed.
Asunto(s)
Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/terapia , Modelos Animales de Enfermedad , Proteínas de Unión al GTP rho/metabolismo , Animales , Trastorno del Espectro Autista/genética , Proteínas Activadoras de GTPasa/metabolismo , Humanos , Proteínas de Unión al GTP rho/químicaRESUMEN
Autism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental disorders with poorly understood etiology that are defined exclusively on the basis of behavioral observations. This disorder has been linked to increased levels of oxidative stress and lower antioxidant capacity. Oxidative stress in autism has been studied at the membrane level and also by measuring products of lipid peroxidation, detoxifying agents (such as glutathione), and antioxidants involved in the defense system against reactive oxygen species (ROS). Several studies have suggested alterations in the activities of antioxidant enzymes such as superoxide dismutase, glutathione peroxidase, and catalase in autism. Additionally, altered glutathione levels and homocysteine/methionine metabolism, increased inflammation, excitotoxicity, as well as mitochondrial and immune dysfunction have been suggested in autism. Moreover, environmental and genetic risk factors may intensify vulnerability to oxidative stress in autism. Collectively, these studies suggest increased oxidative stress in autism that may contribute to the development of this disease both in terms of pathogenesis and clinical symptoms. Antioxidant supplementation, or ways to improve the altered metabolite levels in the interconnected transmethylation and transsulfuration pathways, has been associated with decreased autistic behaviors and severity. This chapter provides a conceptual framework on oxidative stress and antioxidants utility. These types of interventions should be further studied in order to determine their effectiveness at improving metabolic imbalances.
Asunto(s)
Antioxidantes/metabolismo , Trastorno del Espectro Autista/metabolismo , Estrés Oxidativo , Trastorno del Espectro Autista/enzimología , Trastorno Autístico/enzimología , Trastorno Autístico/metabolismo , HumanosRESUMEN
CHD8, which encodes Chromodomain helicase DNA-binding protein 8, is one of a few well-established Autism Spectrum Disorder (ASD) genes. Over 60 mutations have been reported in subjects with variable phenotypes, but little is known concerning genotype-phenotype correlations. We have identified four novel de novo mutations in Chinese subjects: two nonsense variants (c.3562C>T/p.Arg1188X, c.2065C>A/p.Glu689X), a splice site variant (c.4818-1G>A) and a missense variant (c.3502T>A/p.Tyr1168Asn). Three of these were identified from a 445-member ASD cohort by ASD gene panel sequencing of the 96 subjects who remained negative after molecular testing for copy number variation, Rett syndrome, FragileX and tuberous sclerosis complex (TSC). The fourth (p.Glu689X) was detected separately by diagnostic trio exome sequencing. We used diagnostic instruments and a comprehensive review of phenotypes, including prenatal and postnatal growth parameters, developmental milestones, and dysmorphic features to compare these four subjects. In addition to autism, they also presented with prenatal onset macrocephaly, intellectual disability, overgrowth during puberty, sleep disorder, and dysmorphic features, including broad forehead with prominent supraorbital ridges, flat nasal bridge, telecanthus and large ears. For further comparison, we compiled a comprehensive list of CHD8 variants from the literature and databases, which revealed constitutive and somatic truncating variants in the HELIC (Helicase-C) domain in ASD and in cancer patients, respectively, but not in the general population. Furthermore, HELIC domain mutations were associated with a severe phenotype defined by a greater number of clinical features, lower verbal IQ, and a prominent, consistent pattern of overgrowth as measured by weight, height and head circumference. Overall, this study adds to the ASD-associated loss-of-function mutations in CHD8 and highlights the clinical importance of the HELIC domain of CHD8.
Asunto(s)
Trastorno del Espectro Autista/genética , Codón sin Sentido , Proteínas de Unión al ADN/genética , Síndrome del Cromosoma X Frágil/genética , Trastornos del Desarrollo del Lenguaje/genética , Mutación Missense , Fenotipo , Síndrome de Rett/genética , Factores de Transcripción/genética , Esclerosis Tuberosa/genética , Trastorno del Espectro Autista/enzimología , Niño , Femenino , Síndrome del Cromosoma X Frágil/enzimología , Humanos , Trastornos del Desarrollo del Lenguaje/enzimología , Masculino , Dominios Proteicos , Síndrome de Rett/enzimología , Esclerosis Tuberosa/enzimologíaRESUMEN
Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.
Asunto(s)
Trastorno del Espectro Autista/genética , Fosfohidrolasa PTEN/genética , Adolescente , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/patología , Encéfalo/patología , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Mutación de Línea Germinal , Heterocigoto , Humanos , Modelos Lineales , Masculino , Pruebas Neuropsicológicas , Fosfohidrolasa PTEN/metabolismo , Fenotipo , Estados Unidos , Adulto JovenRESUMEN
Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder, characterized by impaired social interaction, repetitive behavior and restricted interests. Although the molecular etiology of ASD remains largely unknown, recent studies have suggested that de novo mutations are significantly involved in the risk of ASD. We and others recently identified spontaneous de novo mutations in PKD2, a protein kinase D family member, in sporadic ASD cases. However, the biological significance of the de novo PKD2 mutations and the role of PKD2 in brain development remain unclear. Here, we performed functional analysis of PKD2 in cortical neuron development using in utero electroporation. PKD2 is highly expressed in cortical neural stem cells in the developing cortex and regulates cortical neuron development, including the neuronal differentiation of neural stem cells and migration of newborn neurons. Importantly, we determined that the ASD-associated de novo mutations impair the kinase activity of PKD2, suggesting that the de novo PKD2 mutations can be a risk factor for the disease by loss of function of PKD2. Our current findings provide novel insight into the molecular and cellular pathogenesis of ASD.
Asunto(s)
Trastorno del Espectro Autista/enzimología , Corteza Cerebral/metabolismo , Neuronas/metabolismo , Canales Catiónicos TRPP/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Desarrollo Embrionario , Células HEK293 , Humanos , Neuronas/citologíaRESUMEN
This review examines our current understanding of autism spectrum disorder (ASD), its prevalence, impact, behavioral treatment, and outcomes. Building on this knowledge, ASD associated with PTEN mutations is introduced and recent human studies of neurobehavioral and neuroimaging findings in patients with PTEN mutations with and without ASD are reviewed. In doing so, we present evidence supporting a model of PTEN loss leading to neurobehavioral deficits, including ASD and intellectual disability. Next, we describe the neurobehavioral spectrum observed across PTEN mutation cases, adding specificity where possible, based on data from recent studies of child and adult PTEN patients. Finally, we end with a discussion of potential clinical recommendations for improving interventions and supports for people with PTEN-ASD and future research avenues for understanding and treating the functional and cognitive deficits in PTEN-ASD.
Asunto(s)
Trastorno del Espectro Autista/genética , Fosfohidrolasa PTEN/genética , Adulto , Trastorno del Espectro Autista/enzimología , Encéfalo/patología , Niño , Mutación de Línea Germinal , Humanos , Discapacidad Intelectual , Pruebas NeuropsicológicasRESUMEN
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by glia over-proliferation, neuro-inflammation, perturbed neural circuitry, and gastrointestinal symptoms. The role of gut dys-biosis in ASD is intriguing and should be elucidated. We investigated the effect of Propionic acid (PPA), a short-chain fatty acid (SCFA) and a product of dys-biotic ASD gut, on human neural stem cells (hNSCs) proliferation, differentiation and inflammation. hNSCs proliferated to 66 neuropsheres when exposed to PPA versus 45 in control. The neurosphere diameter also increased at day 10 post PPA treatment to (Mean: 193.47 um ± SEM: 6.673 um) versus (154.16 um ± 9.95 um) in control, p < 0.001. Pre-treatment with ß-HB, SCFA receptor inhibitor, hindered neurosphere expansion (p < 0.001). While hNSCs spontaneously differentiated to (48.38% ± 6.08%) neurons (Tubulin-IIIß positive) and (46.63% ± 2.5%) glia (GFAP positive), PPA treatment drastically shifted differentiation to 80% GFAP cells (p < 0.05). Following 2 mM PPA exposure, TNF-α transcription increased 4.98 fold and the cytokine increased 3.29 fold compared to control (P < 0.001). Likewise, GPR41 (PPA receptor) and pro-survival p-Akt protein were elevated (p < 0.001). PTEN (Akt inhibitor) level decreased to (0.42 ug/ul ± 0.04 ug/ul) at 2 mM PPA compared to (0.83 ug/ul ± 0.09 ug/ul) in control (p < 0.001). PPA at 2 mM decreased neurite outgrowth to (80.70 um ± 5.5 um) compared to (194.93 um ± 19.7 um) in control. Clearly, the data supports a significant role for PPA in modulating hNSC patterning leading to gliosis, disturbed neuro-circuitry, and inflammatory response as seen in ASD.
Asunto(s)
Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/patología , Gliosis/patología , Inflamación/patología , Neuronas/patología , Fosfohidrolasa PTEN/metabolismo , Propionatos/efectos adversos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Biomarcadores de Tumor/metabolismo , Ácido Butírico/farmacología , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Proteína Ácida Fibrilar de la Glía/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Células-Madre Neurales/citología , Células-Madre Neurales/efectos de los fármacos , Neuritas/efectos de los fármacos , Neuritas/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal/efectos de los fármacos , Tubulina (Proteína)/metabolismoRESUMEN
UBA6 is an alternative enzyme for ubiquitin activation in vertebrates that plays a pivotal role in early mouse development. Previously, we reported that the Uba6 brain-specific knockout (NKO) mouse is a novel autism spectrum disorder (ASD) mouse model that displays decreased social behavior and communication. To determine the therapeutic impact of environmental stimulation in ASDs, we investigated the behavioral and molecular changes of the NKO and control mice after exposure to environmental enrichment and paired housing in different developmental phases. Our results demonstrated that early paired housing could diminish the ASD phenotypes of NKO mice such as impaired nest building and social interaction and anxiety. Additionally, increased histone acetylation in the amygdala was observed in NKO mice after paired housing without a change in Ube3a levels. Our data suggest that paired housing at an early time point can play a crucial role in ameliorating ASD behavior and can be applied in other ASD animal models or clinical settings.
Asunto(s)
Amígdala del Cerebelo/enzimología , Ansiedad/genética , Trastorno del Espectro Autista/genética , Vivienda para Animales , Enzimas Activadoras de Ubiquitina/genética , Acetilación , Animales , Ansiedad/enzimología , Ansiedad/fisiopatología , Ansiedad/prevención & control , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/fisiopatología , Modelos Animales de Enfermedad , Conducta Exploratoria/fisiología , Expresión Génica , Histonas/genética , Histonas/metabolismo , Relaciones Interpersonales , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Noqueados , Comportamiento de Nidificación/fisiología , Ubiquitina/genética , Ubiquitina/metabolismo , Enzimas Activadoras de Ubiquitina/deficiencia , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Loss-of-function mutations in the histone demethylases KDM5A, KDM5B, or KDM5C are found in intellectual disability (ID) and autism spectrum disorders (ASD) patients. Here, we use the model organism Drosophila melanogaster to delineate how KDM5 contributes to ID and ASD. We show that reducing KDM5 causes intestinal barrier dysfunction and changes in social behavior that correlates with compositional changes in the gut microbiota. Therapeutic alteration of the dysbiotic microbiota through antibiotic administration or feeding with a probiotic Lactobacillus strain partially rescues the behavioral, lifespan, and cellular phenotypes observed in kdm5-deficient flies. Mechanistically, KDM5 was found to transcriptionally regulate component genes of the immune deficiency (IMD) signaling pathway and subsequent maintenance of host-commensal bacteria homeostasis in a demethylase-dependent manner. Together, our study uses a genetic approach to dissect the role of KDM5 in the gut-microbiome-brain axis and suggests that modifying the gut microbiome may provide therapeutic benefits for ID and ASD patients.
Asunto(s)
Trastorno del Espectro Autista/microbiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimología , Drosophila melanogaster/inmunología , Microbioma Gastrointestinal , Histona Demetilasas/metabolismo , Mucosa Intestinal/microbiología , Animales , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/inmunología , Trastorno del Espectro Autista/psicología , Conducta Animal , Modelos Animales de Enfermedad , Drosophila , Proteínas de Drosophila/genética , Drosophila melanogaster/microbiología , Drosophila melanogaster/fisiología , Femenino , Histona Demetilasas/genética , Humanos , Mucosa Intestinal/inmunología , Masculino , Conducta SocialRESUMEN
Autism spectrum disorders (ASD) are a group of complex psychiatric disorders, with a proposed gene-environment interaction in their etiology. One mechanism that could explain both the genetic and environmental component is oxidative stress. The aim of our study was to investigate the potential role of common polymorphisms in genes for glutathione transferase A1, M1, T1 and P1 in susceptibility to ASD. We also aimed to explore the possible oxidative stress - specific gene-environment interaction, regarding GST polymorphisms, maternal smoking tobacco during pregnancy (TSDP) and the risk of ASD. This case-control study included 113 children with ASD and 114 age and sex-matched controls. The diagnosis was made based on ICD-10 criteria and verified by Autism Diagnostic Interview - Revised (ADI-R). We investigated GSTA1, GSTM1, GSTP1 and GSTT1 genotypes and explored their individual and combined effects in individuals with ASD. Individual effect of GST genotypes was shown for GSTM1 active genotype decreasing the risk of ASD (OR = 0.554, 95%CI: 0.313-0.983, p = 0.044), and for GSTA1 CC genotype, increasing susceptibility to ASD (OR = 4.132, 95%CI: 1.219-14.012, p = 0.023); the significance was lost when genotype-genotype interactions were added into the logistic regression model. The combination of GSTM1 active and GSTT1 active genotype decreased the risk of ASD (OR = 0.126, 95%CI: 0.029-0.547, p = 0.006), as well as combination of GSTT1 active and GSTP1 llelle (OR = 0.170, 95%CI: 0.029-0.992, p = 0.049). Increased risk of ASD was observed if combination of GSTM1 active and GSTP1 llelle was present (OR = 11.088, 95%CI: 1.745-70.456, p = 0.011). The effect of TSDP was not significant for the risk of ASD, neither individually, nor in interaction with specific GST genotypes. Specific combination of GST genotypes might be associated with susceptibility to ASD, while it appears that maternal smoking during pregnancy does not increase the risk of ASD.
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Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/genética , Predisposición Genética a la Enfermedad , Glutatión Transferasa/genética , Polimorfismo Genético , Fumar Tabaco/efectos adversos , Fumar Tabaco/genética , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Padres , Embarazo , Factores de RiesgoRESUMEN
Opioid peptides released during digestion of dietary proteins such as casein, were suggested to contribute to autism development, leading to the announcement of opioid excess hypothesis of autism. This paper examines role of enzyme proline dipeptidyl peptidase-4 (DPPIV; EC 3.4.14.5) and it is exogenous substrate, ß-casomorphin-7 (BCM7) in autism etiology. Our study included measurements of DPPIV and BCM7 concentrations in serum and urine, which were analyzed with ELISA assays and activity of DPPIV was measured by colorimetric test. The effect of opioid peptides from hydrolysed bovine milk on DPPIV gene expression in peripheral blood mononuclear cells (PBMC) in autistic and healthy children was determined using the Real-Time PCR (Polymerase Chain Reaction) method. Our research included 51 healthy children and 86 children diagnosed with autism spectrum disorder (ASD, ICDF84). We determined that the concentration of BCM7 in serum was significantly, 1.6-fold, higher in the ASD group than in controls (p < 0.0001). Concentration of DPPIV was found to also be significantly higher in serum from ASD children compared to the control group (p < 0.01), while we did not notice significant difference in enzymatic activity of serum DPPIV between the two study groups. We confirmed correlation according to the gender between analyzed parameters. The inspiration for this study emanated from clinical experience of the daily diet role in relieving the symptoms of autism. Despite this, we have concluded that milk-derived opioid peptides and DPPIV are potentially factors in determining the pathogenesis of autism; conducted studies are still limited and require further research.
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Trastorno del Espectro Autista/enzimología , Dipeptidil Peptidasa 4/fisiología , Leche/química , Péptidos Opioides/fisiología , Animales , Trastorno del Espectro Autista/sangre , Trastorno del Espectro Autista/etiología , Niño , Preescolar , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/genética , Endorfinas/sangre , Endorfinas/farmacología , Endorfinas/fisiología , Femenino , Expresión Génica/efectos de los fármacos , Humanos , Leucocitos Mononucleares/enzimología , Masculino , Péptidos Opioides/sangre , Péptidos Opioides/orina , Fragmentos de Péptidos/sangre , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/fisiología , Prolina , Factores SexualesRESUMEN
Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme for the critical process of one-carbon metabolism involving folate and homocysteine metabolisms. It is known that some polymorphism of MTHFR would result in reduction of MTHFR enzyme activity as well as DNA methylation process, later shown to have significant impacts in various psychiatric diseases. However, it is unclear whether the polymorphism of MTHFR could be an independent or an add-on risk factor for specific psychiatric symptoms, such as anxiety, depression, positive, or negative symptoms of schizophrenia, or acts as risk factor for specific psychiatric disorders, such as schizophrenia, major depression, autisms, and bipolar disorders. It is also understudied on whether folate supplements could be an effective treatment for psychiatric patients with defect MTHFR activity. In this review, we not only gathered the most recent discoveries on MTHFR polymorphism and related DNA methylation in various psychiatric disorders, but also highlighted the potential relationships between MTHFR activity and implication of folate-related function in specific mental diseases.
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Trastorno por Déficit de Atención con Hiperactividad , Trastorno del Espectro Autista , Trastorno Bipolar , Trastorno Depresivo , Metilenotetrahidrofolato Reductasa (NADPH2) , Esquizofrenia , Animales , Trastorno por Déficit de Atención con Hiperactividad/enzimología , Trastorno por Déficit de Atención con Hiperactividad/genética , Trastorno del Espectro Autista/enzimología , Trastorno del Espectro Autista/genética , Trastorno Bipolar/enzimología , Trastorno Bipolar/genética , Trastorno Depresivo/enzimología , Trastorno Depresivo/genética , Humanos , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Esquizofrenia/enzimología , Esquizofrenia/genéticaRESUMEN
Synaptic cytoskeleton dysfunction represents a common pathogenesis in neurodevelopmental disorders, such as autism spectrum disorder (ASD). The serine/threonine kinase PAK2 is a critical regulator of cytoskeleton dynamics. However, its function within the central nervous system and its role in ASD pathogenesis remain undefined. Here, we found that Pak2 haploinsufficiency resulted in markedly decreased synapse densities, defective long-term potentiation, and autism-related behaviors in mice. Phosphorylation levels of key actin regulators LIMK1 and cofilin, together with their mediated actin polymerization, were reduced in Pak2+/-mice. We identified one de novo PAK2 nonsense mutation that impaired PAK2 function in vitro and in vivo and four de novo copy-number deletions containing PAK2 in large cohorts of patients with ASD. PAK2 deficiency extensively perturbed functional networks associated with ASD by regulating actin cytoskeleton dynamics. Our genetic and functional results demonstrate a critical role of PAK2 in brain development and autism pathogenesis.