The need for a comprehensive molecular characterization of autism spectrum disorders

Broek, Jantine A.C.; Brombacher, Eva; Stelzhammer, Viktoria; Guest, Paul C.; Rahmoune, Hassan; Bahn, Sabine

doi:10.1017/s146114571300117x

Cited by 16 publications

(20 citation statements)

References 272 publications

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“…As in ASD ethiopathogenesis may involved both environment and genetics factors (Gentile et al, 2013), the affected zebrafish larvae showing circle swimming may have genetic susceptibility against MSG, which needs further studies to clarify. Many mutations associated with autism have been characterized (Broek et al, 2014), however, which mutation(s) involved in MSG susceptibility causing stereotypic behavior changes are to be identified.…”

Section: Msg Increased Circle Swimming Events and Decreased Locomotormentioning

confidence: 99%

Monosodium Glutamate Exposure at Early Developmental Stage Increases Apoptosis and Stereotypic Behavior Risks on Zebrafish (Danio Rerio) Larvae

Kurnianingsih

2016

Indonesian J. Pharm.

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Excessive glutamate may give neurotoxic effects and contribute to Autism spectrum disorder(ASD). In this study, we investigated prolonged exposure effects of 10 µg/mL Monosodium Glutamate (MSG) on intracellular calcium level, bax, bcl-2, ratio of bax/bcl-2 genes expression, caspase-3, apoptosis of brain cells and stereotypic behavior of Zebrafish (Danio rerio) larvae at early developmental stages. Genes expression were determined by real time PCR, caspase-3 using ELISA, intracellular Ca 2+ and apoptotic cells of brain using confocal microscopy, locomotor activity by using crossing lines assay whereas stereotypic behavior by circle swimming. The results indicated that MSG exposure increased brain bax and bcl-2; and caspase-3; intracellular Ca 2+ ; and apoptosis; stereotypic behavior; and decreased locomotor activity. Termination of MSG treatments resulted in recovery of bax, bcl-2, caspase-3 basal levels and stereotypic behavior. In conclusion, MSG exposure at early embryonic stage increased brain cell damage and risk of behavior changes.

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Section: Msg Increased Circle Swimming Events and Decreased Locomotormentioning

confidence: 99%

Monosodium Glutamate Exposure at Early Developmental Stage Increases Apoptosis and Stereotypic Behavior Risks on Zebrafish (Danio Rerio) Larvae

Kurnianingsih

2016

Indonesian J. Pharm.

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“…Understanding the molecular mechanisms involved in ASD is the subject of transcriptomic and proteomic research, both of which have indicated abnormal neuronal development and inflammation (Broek et al, 2014). Transcriptomic studies, which use cDNA microarray and RNA sequencing, have identified dysregulated hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in individuals with ASD, which have known functions in synaptic plasticity (Isaac et al, 2007;Purcell et al, 2001;van Spronsen and Hoogenraad, 2010).…”

Section: Molecular Datamentioning

confidence: 99%

“…Transcriptomic studies, which use cDNA microarray and RNA sequencing, have identified dysregulated hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in individuals with ASD, which have known functions in synaptic plasticity (Isaac et al, 2007;Purcell et al, 2001;van Spronsen and Hoogenraad, 2010). Disruptions to the gamma-aminobutyric acid (GABA) receptor system, which is involved in signal transduction and cellular adhesion, have also been found in ASD samples (Broek et al, 2014;Voineagu, 2012;Voineagu et al, 2011).…”

Section: Molecular Datamentioning

confidence: 99%

“…Proteomic studies have investigated protein expression in serum, plasma, and postmortem brains of individuals with ASD using techniques such as mass spectrometry and immunoassay (Broek et al, 2014;Schwarz et al, 2011;Taurines et al, 2010). Studies have found increased levels of proteins involved in synapse formation, such as brain-derived neurotrophic factor (BDNF) and glial fibrillary acidic protein (GFAP) in ASD samples (Chauhan et al, 2011;Correia et al, 2010;Fatemi et al, 2002;Riikonen, 2003;Schwarz et al, 2011;Thanseem et al, 2012).…”

Section: Molecular Datamentioning

confidence: 99%

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The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

Higdon

Earl

Stanberry

et al. 2015

OMICS: A Journal of Integrative Biology

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Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.

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“…Finally, changes in mitochondrial and energy pathways have also been reported [19], although it has been hypothesized that these changes may be secondary to an as yet unidentified disease process [20]. Several independent studies have corroborated that creatine kinase (CK), an enzyme important for energy homeostasis, is one of the most robust chemical changes in autism and this is likely to parallel changes in synaptic remodelling [21]. …”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of post mortem brain tissue from autism patients: evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins

et al. 2014

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BackgroundAutism is a neurodevelopmental disorder characterized by impaired language, communication and social skills. Although genetic studies have been carried out in this field, none of the genes identified have led to an explanation of the underlying causes. Here, we have investigated molecular alterations by proteomic profiling of post mortem brain samples from autism patients and controls. The analysis focussed on prefrontal cortex and cerebellum as previous studies have found that these two brain regions are structurally and functionally connected, and they have been implicated in autism.MethodsPost mortem prefrontal cortex and cerebellum samples from autism patients and matched controls were analysed using selected reaction monitoring mass spectrometry (SRM-MS). The main objective was to identify significantly altered proteins and biological pathways and to compare these across these two brain regions.ResultsTargeted SRM-MS resulted in identification of altered levels of proteins related to myelination, synaptic vesicle regulation and energy metabolism. This showed decreased levels of the immature astrocyte marker vimentin in both brain regions, suggesting a decrease in astrocyte precursor cells. Also, decreased levels of proteins associated with myelination and increased synaptic and energy-related proteins were found in the prefrontal cortex, indicative of increased synaptic connectivity. Finally, opposite directional changes were found for myelination and synaptic proteins in the cerebellum.ConclusionThese findings suggest altered structural and/or functional connectivity in the prefrontal cortex and cerebellum in autism patients, as shown by opposite effects on proteins involved in myelination and synaptic function. Further investigation of these findings could help to increase our understanding of the mechanisms underlying autism relating to brain connectivity, with the ultimate aim of facilitating novel therapeutic approaches.

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The need for a comprehensive molecular characterization of autism spectrum disorders

Cited by 16 publications

References 272 publications

Monosodium Glutamate Exposure at Early Developmental Stage Increases Apoptosis and Stereotypic Behavior Risks on Zebrafish (Danio Rerio) Larvae

Monosodium Glutamate Exposure at Early Developmental Stage Increases Apoptosis and Stereotypic Behavior Risks on Zebrafish (Danio Rerio) Larvae

The Promise of Multi-Omics and Clinical Data Integration to Identify and Target Personalized Healthcare Approaches in Autism Spectrum Disorders

Proteomic analysis of post mortem brain tissue from autism patients: evidence for opposite changes in prefrontal cortex and cerebellum in synaptic connectivity-related proteins

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