scholarly journals Fmr1 translationally activates stress-sensitive mRNAs encoding large proteins in oocytes and neurons

2020 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Acute Stress ◽  
Critical Role ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Translation Elongation ◽  
General Role ◽  
Large Proteins ◽  
Mouse Cortex ◽  
Spectrum Disorders ◽  
Translational Activator

AbstractMutations in Fmr1 are the leading heritable cause of intellectual disability and autism spectrum disorder. We previously found that Fmr1 acts as a ∼2-fold activator of translation of large proteins in Drosophila oocytes, in contrast to its proposed role as a repressor of translation elongation. Here, we show that genes associated with autism spectrum disorders tend to be dosage-sensitive and encode proteins that are larger than average. Reanalysis of Fmr1 KO mouse cortex ribosome profiling data demonstrates that autism-associated mRNAs encoding large proteins exhibit a concordant reduction in ribosome footprints, consistent with a general role for Fmr1 as a translational activator. We find no evidence that differential ribosomal pausing affects translational output in Fmr1-deficient Drosophila oocytes or mouse cortex. Furthermore, long Fmr1 target transcripts are preferentially enriched in stress granules upon acute stress. Our data thus identify a critical role for Fmr1 in promoting the translation of long, stress-sensitive, autism-associated mRNAs.

Critical role of dysfunctional mitochondria and defective mitophagy in autism spectrum disorders

2021 ◽  
Vol 168 ◽  
pp. 138-145
Author(s):  
Yuan-Mei Wang ◽  
Ming-Yue Qiu ◽  
Qing Liu ◽  
Huang Tang ◽  
Hong-Feng Gu
Keyword(s):  
Autism Spectrum Disorders ◽  
Critical Role ◽  
Autism Spectrum ◽  
Spectrum Disorders

scholarly journals Is eye contact the key to the social brain?

2010 ◽  
Vol 33 (6) ◽  
pp. 458-459 ◽  
Author(s):  
Atsushi Senju ◽  
Mark H. Johnson
Keyword(s):  
Autism Spectrum Disorders ◽  
Social Cognition ◽  
Face Processing ◽  
Critical Role ◽  
Eye Contact ◽  
Autism Spectrum ◽  
Social Brain ◽  
Cortical Areas ◽  
The Social ◽  
Spectrum Disorders

AbstractEye contact plays a critical role in many aspects of face processing, including the processing of smiles. We propose that this is achieved by a subcortical route, which is activated by eye contact and modulates the cortical areas involve in social cognition, including the processing of facial expression. This mechanism could be impaired in individuals with autism spectrum disorders.

scholarly journals Do Animals Perceive Human Developmental Disabilities? Guinea Pigs’ Behaviour with Children with Autism Spectrum Disorders and Children with Typical Development. A Pilot Study

Animals ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 522
Author(s):  
Marine Grandgeorge ◽  
Elodie Dubois ◽  
Zarrin Alavi ◽  
Yannig Bourreau ◽  
Martine Hausberger
Keyword(s):  
Autism Spectrum Disorders ◽  
Developmental Disabilities ◽  
Guinea Pigs ◽  
Acute Stress ◽  
Time Budget ◽  
Well Being ◽  
Autism Spectrum ◽  
Typical Development ◽  
Human Animal ◽  
Spectrum Disorders

Some cues used by humans and animals during human-animal interactions may have significant effects, modulating these interactions (e.g., gaze direction, heart rate). This study aimed to determine whether an animal in human-animal interactions is capable of “perceiving” its human partner’s potential developmental “disabilities”. To test this hypothesis, we studied guinea pigs (GP) behaviours in the presence of 44 6-to-12-year-old children with either typical development (TD children) or with autism spectrum disorders (ASD children). Thus, we recorded the GP behaviours during the entire session (to establish their time budget) and focused in particular on the onset and end of physical interactions. The GP behaviours (e.g., feeding, resting, self-grooming, exploring) were not significantly different between the two groups of children during the whole session. GP behaviours in the presence of children differed slightly when encountering ASD children versus TD children: more positive behaviours toward ASD children at the onset, more feeding and resting in the presence of TD children toward the end of an interaction. TD children showed longer-lasting interactions. One could explain this by GP curiosity toward ASD children behaviours (e.g., no marked behaviours such as attempts to touch), whereas GPs seemed calmer at the end with TD children (i.e., interacting with ASD children may be a little stressful). This partly gave support to our study’s hypothesis. GPs seemed to perceive developmental disabilities during a first encounter with children and to adjust their behaviours to that of children. We discuss the issues of animal training, animals’ well-being and acute stress, whether they are pets or used in animal-assisted interventions. Further studies (on pets or animal-assisted interventions) are warranted.

Impact of DRD2 polymorphisms on prolactin level in risperidone-treated Thai children and adolescent with autism spectrum disorders

2016 ◽  
Vol 33 (S1) ◽  
pp. S93-S93
Author(s):  
C. Sukasem ◽  
Y. Hongkaew
Keyword(s):  
Autism Spectrum Disorders ◽  
Children And Adolescents ◽  
Prolactin Level ◽  
Critical Role ◽  
Autism Spectrum ◽  
Nucleotide Polymorphisms ◽  
Genotype Frequencies ◽  
Adolescents With Autism ◽  
Spectrum Disorders ◽  
The Impact

IntroductionA large number of studies have reported that the prolactin concentration was significantly increased in the Taq1A A1 allele carriers because several reports revealed that individuals with the DRD2 Taq1A A1 allele have a reduced density of brain D2 receptors.ObjectiveThe main aim of this study was to identify the impact of pharmacogenetic markers associated with prolactin concentration in risperidone-treated children and adolescents with autism spectrum disorders.MethodsOne hundred and forty-seven children and adolescents with autism, aged 3 to 19, received risperidone. The clinical data of patients were recorded from medical records. Prolactin levels were measured by chemiluminescence immunoassay. Three CYP2D6 single nucleotide polymorphisms (SNPs), CYP2D6*4 (1846G>A), *10 (100C>T), and *41 (2988G>A), one gene deletion (*5), and DRD2 Taq1A (rs1800497) polymorphism were genotyped by TaqMan real-time PCR.ResultsThe three common allelic frequencies were CYP2D6*10 (55.10%), *1 (32.65%) and *5 (6.12%), respectively. Patients were grouped according to their CYP2D6 genotypes. The DRD2 genotype frequencies were Taq1A A2A2 (38.77%), A1A2 (41.50%), and A1A1 (19.73%), respectively. There were statistically significant differences in prolactin level of patients among the three groups (P = 0.033). The median prolactin level in patients with DRD2 Taq1A A2A2 (17.80 ng/mL) was significantly higher than A1A2 (17.10 ng/mL) and A1A1 (12.70 ng/mL).ConclusionDRD2 Taq1A A2A2 polymorphisms may be a critical role in an influence prolactin elevation during risperidone treatment in ASD.Disclosure of interestThe authors have not supplied their declaration of competing interest.

scholarly journals A critical role of brain network architecture in a continuum model of autism spectrum disorders spanning from healthy individuals with genetic liability to individuals with ASD

2021 ◽  
Author(s):  
Budhachandra Khundrakpam ◽  
Neha Bhutani ◽  
Uku Vainik ◽  
Noor B Al-Sharif ◽  
Alain Dagher ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Network Architecture ◽  
Continuum Model ◽  
Critical Role ◽  
Autism Spectrum ◽  
Brain Network ◽  
Healthy Individuals ◽  
Polygenic Risk ◽  
Spectrum Disorders

Studies have shown cortical alterations in individuals with autism spectrum disorders (ASD) as well as in individuals with high polygenic risk for ASD. An important addition to the study of altered cortical anatomy is the investigation of the underlying brain network architecture that may reveal brain-wide mechanisms in ASD and in polygenic risk for ASD. Such an approach has been proven useful in other psychiatric disorders by revealing that brain network architecture shapes (to an extent) the disorder-related cortical alterations. This study uses data from a clinical dataset: 560 male subjects (266 individuals with ASD and 294 healthy individuals, CTL, mean age at 17.2 years) from the Autism Brain Imaging Data Exchange database, and data of 391 healthy individuals (207 males, mean age at 12.1 years) from the Pediatric Imaging, Neurocognition and Genetics database. ASD-related cortical alterations (group difference, ASD-CTL, in cortical thickness) and cortical correlates of polygenic risk for ASD were assessed, and then statistically compared with structural connectome-based network measures (such as hubs) using spin permutation tests. Next, we investigated whether polygenic risk for ASD could be predicted by network architecture by building machine-learning based prediction models, and whether the top predictors of the model were identified as disease epicenters of ASD. We observed that ASD-related cortical alterations as well as cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. We also observed that age progression of ASD-related cortical alterations and cortical correlates of polygenic risk for ASD implicated cortical hubs more strongly than non-hub regions. Further investigation revealed that structural connectomes predicted polygenic risk for ASD (r=0.30, p<0.0001), and two brain regions (the left inferior parietal and left suparmarginal) with top predictive connections were identified as disease epicenters of ASD. Our study highlights a critical role of network architecture in a continuum model of ASD spanning from healthy individuals with genetic risk to individuals with ASD. Our study also highlights the strength of investigating polygenic risk scores in addition to multi-modal neuroimaging measures to better understand the interplay between genetic risk and brain alterations associated with ASD.

scholarly journals Fragile X mental retardation protein is a size-dependent translational activator

2018 ◽  
Author(s):  
Ethan J. Greenblatt ◽  
Allan C. Spradling
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Ovarian Follicle ◽  
Autism Spectrum ◽  
Ribosome Profiling ◽  
Large Proteins ◽  
Fragile X Mental Retardation ◽  
Stored Mrna ◽  
Neural Dysfunction

SummaryFMR1 enhances translation of large neural/oocyte proteinsMutations in the highly conserved Fragile X mental retardation gene (Fmr1) cause the most common inherited human intellectual disability/autism spectrum disorder. Fmr1 is also needed for ovarian follicle development, and lesions are the largest genetic cause of premature ovarian failure (POF). FMR1 associates with ribosomes and is thought to repress translation, but identifying functional targets has been difficult. We analyzed FMR1’s role in quiescent Drosophila oocytes stored prior to ovulation, cells that depend entirely on translation of stored mRNA. Ribosome profiling revealed that in quiescent oocytes FMR1 stimulates the translation of large proteins, including at least twelve proteins whose human homologs are associated with dominant intellectual disability disorders, and 25 others associated with neural dysfunction. Knockdown of Fmr1 in unstored oocytes did not affect embryo development, but more than 50% of embryos derived from stored oocytes lacking FMR1 developed severe neural defects. Fmr1’s previously unappreciated role promoting the translation of large proteins from stored mRNAs in oocytes and neurons may underlie POF as well as multiple aspects of neural dysfunction.

scholarly journals Organization of the Environment for Teaching Children with ASD

2018 ◽  
Vol 16 (1) ◽  
pp. 13-17
Author(s):  
O.V. Zagumennaya ◽  
A.V. Vasilyeva ◽  
V.V. Kisten ◽  
O.V. Petrova
Keyword(s):  
Autism Spectrum Disorders ◽  
Educational Program ◽  
Critical Role ◽  
Children With Autism ◽  
First Grade ◽  
Autism Spectrum ◽  
Resource Center ◽  
Class Environment ◽  
Spectrum Disorders ◽  
Program Version

A structured environment plays a critical role in the education of children with autism spectrum disorders. The experience of structuring of the class environment in the Federal Resource Center for the Organization of Comprehensive Support for Children with Autism Spectrum Disorders is presented. The material is approbated in work with children who entered the first grade of the school. The Central Psychological-Medical Pedagogical Commission recommended the Adapted Basic Educational Program (version 8.3) for these children.

scholarly journals Critical Role of the Maternal Immune System in the Pathogenesis of Autism Spectrum Disorder

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 557
Author(s):  
Davide Ravaccia ◽  
Taravat Ghafourian
Keyword(s):  
Immune System ◽  
Critical Role ◽  
Epidemiological Studies ◽  
Autism Spectrum ◽  
Therapeutic Interventions ◽  
Maternal Immune Activation ◽  
Maternal Immune System ◽  
Clinical Presentations ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterised by impairments in communication, social interaction, and the presence of restrictive and repetitive behaviours. Over the past decade, most of the research in ASD has focused on the contribution of genetics, with the identification of a variety of different genes and mutations. However, the vast heterogeneity in clinical presentations associated with this disorder suggests that environmental factors may be involved, acting as a “second hit” in already genetically susceptible individuals. To this regard, emerging evidence points towards a role for maternal immune system dysfunctions. This literature review considered evidence from epidemiological studies and aimed to discuss the pathological relevance of the maternal immune system in ASD by looking at the proposed mechanisms by which it alters the prenatal environment. In particular, this review focuses on the effects of maternal immune activation (MIA) by looking at foetal brain-reactive antibodies, cytokines and the microbiome. Despite the arguments presented here that strongly implicate MIA in the pathophysiology of ASD, further research is needed to fully understand the precise mechanisms by which they alter brain structure and behaviour. Overall, this review has not only shown the importance of the maternal immune system as a risk factor for ASD, but more importantly, has highlighted new promising pathways to target for the discovery of novel therapeutic interventions for the treatment of such a life-changing disorder.

scholarly journals Regulatory T lymphocytes/Th17 lymphocytes imbalance in autism spectrum disorders: evidence from a meta-analysis

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pierre Ellul ◽  
Michelle Rosenzwajg ◽  
Hugo Peyre ◽  
Gwladys Fourcade ◽  
Encarnita Mariotti-Ferrandiz ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
T Lymphocytes ◽  
Meta Analysis ◽  
Critical Role ◽  
Autism Spectrum ◽  
Regulatory T Lymphocytes ◽  
Immune System Dysfunction ◽  
Th17 Lymphocytes ◽  
Significant Difference ◽  
Spectrum Disorders

Abstract Background Immune system dysfunction has been proposed to play a critical role in the pathophysiology of autism spectrum disorders (ASD). Conflicting reports of lymphocyte subpopulation abnormalities have been described in numerous studies of patients with ASD. To better define lymphocytes abnormalities in ASD, we performed a meta-analysis of the lymphocyte profiles from subjects with ASD. Methods We used the PRISMA recommendations to query PubMed, Embase, PsychoINFO, BIOSIS, Science Direct, Cochrane CENTRAL, and Clinicaltrials.gov for terms related to clinical diagnosis of ASD and to lymphocytes’ populations. We selected studies exploring lymphocyte subpopulations in children with ASD. The search protocol has been registered in the international Prospective Register of Systematic Reviews (CRD42019121473). Results We selected 13 studies gathering 388 ASD patients and 326 healthy controls. A significant decrease in the CD4+ lymphocyte was found in ASD patients compared to controls [− 1.51 (95% CI − 2.99; − 0.04) p = 0.04] (I2 = 96% [95% CI 94.6, 97.7], p < 0.01). No significant difference was found for the CD8+ T, B and natural killer lymphocytes. Considering the CD4+ subpopulation, there was a significant decrease in regulatory T lymphocytes (Tregs) in ASD patients (n = 114) compared to controls (n = 107) [− 3.09 (95% CI − 4.41; − 1.76) p = 0.0001]; (I2 = 90.9%, [95% CI 76.2, 96.5], p < 0.0001) associated with an increase oin the Th17 lymphocytes (ASD; n = 147 controls; n = 128) [2.23 (95% CI 0.79; 3.66) p = 0,002] (I2 = 95.1% [95% CI 90.4, 97.5], p < 0.0001). Limitations Several factors inducing heterogeneity should be considered. First, differences in the staining method may be responsible for a part in the heterogeneity of results. Second, ASD population is also by itself heterogeneous, underlying the need of studying sub-groups that are more homogeneous. Conclusion Our meta-analysis indicates defects in CD4+ lymphocytes, specifically decrease oin Tregs and increase in Th17 in ASD patients and supports the development of targeted immunotherapies in the field of ASD.

scholarly journals FMRP inhibits translation elongation independent of mRNA G-quadruplexes

2022 ◽  
Author(s):  
MaKenzie R. Scarpitti ◽  
Julia E. Warrick ◽  
Michael G. Kearse
Keyword(s):  
Rna Binding ◽  
Fragile X ◽  
Mrna Localization ◽  
Autism Spectrum ◽  
Rna Sequences ◽  
Translation Elongation ◽  
Mental Retardation Protein ◽  
Work Shifts ◽  
Spectrum Disorders ◽  
Reporter Mrna

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome, the leading form of inherited intellectual disability and the most common monogenic cause of autism spectrum disorders. FMRP is an RNA-binding protein that controls neuronal mRNA localization and translation. Notably, FMRP is thought to inhibit translation elongation after being recruited to target transcripts via binding RNA G-quadruplexes (G4s) within the coding sequence. Here we directly tested this model and report that FMRP inhibits translation elongation independent of mRNA G4s. Furthermore, we found that the RGG box motif together with its natural C-terminal domain forms a non-canonical RNA-binding domain (ncRBD) that binds reporter mRNA and all four polymeric RNA sequences. The ncRBD is essential for FMRP to inhibit translation. Transcripts that are bound by FMRP through the ncRBD co-sediment with heavy polysomes, which is consistent with stalling elongating ribosomes and a subsequent accumulation of slowed polysomes. Together, this work shifts our understanding of how FMRP inhibits translation elongation and supports a model where repression is driven by local FMRP and mRNA concentrations rather than target mRNA sequence.

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