1. Chiocchetti AG, Haslinger D, Boesch M, Karl T, Wiemann S, Freitag CM, Poustka F, Scheibe B, Bauer JW, Hintner H, Breitenbach M, Kellermann J, Lottspeich F, Klauck SM, Breitenbach-Koller L. {{Protein signatures of oxidative stress response in a patient specific cell line model for autism}}. {Mol Autism};2014 (Feb 10);5(1):10.
BACKGROUND: Known genetic variants can account for 10% to 20% of all cases with autism spectrum disorders (ASD). Overlapping cellular pathomechanisms common to neurons of the central nervous system (CNS) and in tissues of peripheral organs, such as immune dysregulation, oxidative stress and dysfunctions in mitochondrial and protein synthesis metabolism, were suggested to support the wide spectrum of ASD on unifying disease phenotype. Here, we studied in patient-derived lymphoblastoid cell lines (LCLs) how an ASD-specific mutation in ribosomal protein RPL10 (RPL10[H213Q]) generates a distinct protein signature. We compared the RPL10[H213Q] expression pattern to expression patterns derived from unrelated ASD patients without RPL10[H213Q] mutation. In addition, a yeast rpl10 deficiency model served in a proof-of-principle study to test for alterations in protein patterns in response to oxidative stress. METHODS: Protein extracts of LCLs from patients, relatives and controls, as well as diploid yeast cells hemizygous for rpl10, were subjected to two-dimensional gel electrophoresis and differentially regulated spots were identified by mass spectrometry. Subsequently, Gene Ontology database (GO)-term enrichment and network analysis was performed to map the identified proteins into cellular pathways. RESULTS: The protein signature generated by RPL10[H213Q] is a functionally related subset of the ASD-specific protein signature, sharing redox-sensitive elements in energy-, protein- and redox-metabolism. In yeast, rpl10 deficiency generates a specific protein signature, harboring components of pathways identified in both the RPL10[H213Q] subjects’ and the ASD patients’ set. Importantly, the rpl10 deficiency signature is a subset of the signature resulting from response of wild-type yeast to oxidative stress. CONCLUSIONS: Redox-sensitive protein signatures mapping into cellular pathways with pathophysiology in ASD have been identified in both LCLs carrying the ASD-specific mutation RPL10[H213Q] and LCLs from ASD patients without this mutation. At pathway levels, this redox-sensitive protein signature has also been identified in a yeast rpl10 deficiency and an oxidative stress model. These observations point to a common molecular pathomechanism in ASD, characterized in our study by dysregulation of redox balance. Importantly, this can be triggered by the known ASD-RPL10[H213Q] mutation or by yet unknown mutations of the ASD cohort that act upstream of RPL10 in differential expression of redox-sensitive proteins.
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2. Choi J, Ababon MR, Soliman M, Lin Y, Brzustowicz LM, Matteson PG, Millonig JH. {{Autism Associated Gene, ENGRAILED2, and Flanking Gene Levels Are Altered in Post-Mortem Cerebellum}}. {PLoS One};2014;9(2):e87208.
BACKGROUND: Previous genetic studies demonstrated association between the transcription factor ENGRAILED2 (EN2) and Autism Spectrum Disorder (ASD). Subsequent molecular analysis determined that the EN2 ASD-associated haplotype (rs1861972-rs1861973 A-C) functions as a transcriptional activator to increase gene expression. EN2 is flanked by 5 genes, SEROTONIN RECEPTOR5A (HTR5A), INSULIN INDUCED GENE1 (INSIG1), CANOPY1 HOMOLOG (CNPY1), RNA BINDING MOTIF PROTEIN33 (RBM33), and SONIC HEDGEHOG (SHH). These flanking genes are co-expressed with EN2 during development and coordinate similar developmental processes. To investigate if mRNA levels for these genes are altered in individuals with autism, post-mortem analysis was performed. METHODS: qRT-PCR quantified mRNA levels for EN2 and the 5 flanking genes in 78 post-mortem cerebellar samples. mRNA levels were correlated with both affection status and rs1861972-rs1861973 genotype. Molecular analysis investigated whether EN2 regulates flanking gene expression. RESULTS: EN2 levels are increased in affected A-C/G-T individuals (p = .0077). Affected individuals also display a significant increase in SHH and a decrease in INSIG1 levels. Rs1861972-rs1861973 genotype is correlated with significant increases for SHH (A-C/G-T) and CNPY1 (G-T/G-T) levels. Human cell line over-expression and knock-down as well as mouse knock-out analysis are consistent with EN2 and SHH being co-regulated, which provides a possible mechanism for increased SHH post-mortem levels. CONCLUSIONS: EN2 levels are increased in affected individuals with an A-C/G-T genotype, supporting EN2 as an ASD susceptibility gene. SHH, CNPY1, and INSIG1 levels are also significantly altered depending upon affection status or rs1861972-rs1861973 genotype. Increased EN2 levels likely contribute to elevated SHH expression observed in the post-mortem samples.
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3. Kuzmanovic B, Schilbach L, Georgescu AL, Kockler H, Santos NS, Shah NJ, Bente G, Fink GR, Vogeley K. {{Dissociating animacy processing in high-functioning autism: Neural correlates of stimulus properties and subjective ratings}}. {Soc Neurosci};2014 (Feb 10)
When movements indicate meaningful actions, even nonbiological objects induce the impression of « having a mind » or animacy. This basic social ability was investigated in adults with high-functioning autism (HFA, n = 13, and matched controls, n = 13) by systematically varying motion properties of simple geometric shapes. Critically, trial-by-trial variations of (1) motion complexity of stimuli, and of (2) participants’ individual animacy ratings were separately correlated with neural activity to dissociate cognitive strategies relying more closely on stimulus analysis vs. subjective experience. Increasing motion complexity did not yield any significant group differences, and in both groups, it correlated with neural activity in regions involved in perceptual and evaluative processing, including the ventral medial prefrontal cortex (mPFC), superior temporal gyrus (STG) and posterior cingulate cortex (PCC). In contrast, although there were no significant behavioral differences between the groups, increasing animacy ratings correlated with neural activity in the insula, STG, amygdala, dorsal mPFC and PCC more strongly in controls than in HFA. These results indicate that in HFA the evaluation of stimulus properties cuing for animacy is intact, while increasing subjective ratings do not seem to be robustly related to social processing, including spontaneous mental state inferences and experience of salience.
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4. Lavelle TA, Weinstein MC, Newhouse JP, Munir K, Kuhlthau KA, Prosser LA. {{Economic Burden of Childhood Autism Spectrum Disorders}}. {Pediatrics};2014 (Feb 10)
OBJECTIVE: To estimate the associations between autism spectrum disorder (ASD) diagnoses and service use, caregiver time, and cost outcomes. METHODS: We used national data from the Medical Expenditure Panel Survey linked to the National Health Interview Survey and a study-specific survey to estimate the annual utilization and costs for health care, school, ASD-related therapy, family-coordinated services, as well as caregiver time in children aged 3 to 17 years, with and without parent-reported ASD. Regression analyses estimated the association between ASD diagnosis and cost, controlling for child gender, age, race/ethnicity, insurance status, household income, country region and urban/rural classification, and non-ASD-related illnesses. RESULTS: Children with parent-reported ASD had higher levels of health care office visits and prescription drug use compared with children without ASD (P < .05). A greater proportion of children in the ASD group used special educational services (76% vs 7% in the control group, P < .05). After adjusting for child demographic characteristics and non-ASD-associated illnesses, ASD was associated with $3020 (95% confidence interval [CI]: $1017-$4259) higher health care costs and $14 061 (95% CI: $4390-$24 302) higher aggregate non-health care costs, including $8610 (95% CI: $6595-$10 421) higher school costs. In adjusted analyses, parents who reported that their child had ASD did not have significantly higher out-of-pocket costs or spend more time on caregiving activities compared with control parents. CONCLUSIONS: The economic burden associated with ASD is substantial and can be measured across multiple sectors of our society. Previous analyses that focused on health care underestimated this economic burden, particularly for school systems.
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5. Ruysschaert L, Warreyn P, Wiersema JR, Oostra A, Roeyers H. {{Exploring the Role of Neural Mirroring in Children with Autism Spectrum Disorder}}. {Autism Res};2014 (Feb 10)
Investigating the underlying neural mechanisms of autism spectrum disorder (ASD) has recently been influenced by the discovery of mirror neurons. These neurons, active during both observation and execution of actions, are thought to play a crucial role in imitation and other social-communicative skills that are often impaired in ASD. In the current electroencephalographic study, we investigated mu suppression, indicating neural mirroring in children with ASD between the ages of 24 and 48 months and age-matched typically developing children, during observation of goal-directed actions and non-goal-directed mimicked hand movements, as well as during action execution. Results revealed no significant group differences with significant central mu suppression in the ASD children and control children during both execution and observation of goal-directed actions and during observation of hand movements. Furthermore, no significant correlations between mu suppression on one hand and quality of imitation, age, and social communication questionnaire scores on the other hand were found. These findings challenge the « broken mirror » hypothesis of ASD, suggesting that impaired neural mirroring is not a distinctive feature of ASD. Autism Res 2014, : – . (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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6. Yalcin O. {{Micturition Difficulty and Urinary Retention Associated with Aripiprazole and Citalopram Treatment in a Male Adolescent with Asperger Syndrome}}. {J Child Adolesc Psychopharmacol};2014 (Feb 10)
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7. Zhou Z, Cao M, Guo Y, Zhao L, Wang J, Jia X, Li J, Wang C, Gabriel G, Xue Q, Yi Y, Cui S, Jin Q, Deng T. {{Fragile X mental retardation protein stimulates ribonucleoprotein assembly of influenza A virus}}. {Nat Commun};2014 (Feb 10);5:3259.
The ribonucleoprotein (RNP) of the influenza A virus is responsible for the transcription and replication of viral RNA in the nucleus. These processes require interplay between host factors and RNP components. Here, we report that the Fragile X mental retardation protein (FMRP) targets influenza virus RNA synthesis machinery and facilitates virus replication both in cell culture and in mice. We demonstrate that FMRP transiently associates with viral RNP and stimulates viral RNP assembly through RNA-mediated interaction with the nucleoprotein. Furthermore, the KH2 domain of FMRP mediates its association with the nucleoprotein. A point mutation (I304N) in the KH2 domain, identified from a Fragile X syndrome patient, disrupts the FMRP-nucleoprotein association and abolishes the ability of FMRP to participate in viral RNP assembly. We conclude that FMRP is a critical host factor used by influenza viruses to facilitate viral RNP assembly. Our observation reveals a mechanism of influenza virus RNA synthesis and provides insights into FMRP functions.
