Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

Bakoš, Ján; Bačová, Zuzana; Grant, Stephen G.; Castejón, Ana M.; Ostatníková, Daniela

doi:10.1007/s12017-015-8357-7

Cited by 56 publications

(47 citation statements)

References 66 publications

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“…Neuronal migration and morphogenesis defects in ASD contribute to an altered cortical connectivity in different brain regions [45] [46], as the well-known prefrontal area [47]. Therefore, in the developing brain, a premature alteration in neuronal plasticity, affecting mostly cortical regions involved in cognitive and behavioral functions, might trigger the autistic phenotype [48] [49].…”

Section: Discussionmentioning

confidence: 99%

A novel data-driven approach reveals gene networks and biological processes underlying autism

Gialloreti¹,

Enea²,

Micco³

et al. 2020

Preprint

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Background: Developments in gene-hunting techniques identified several ASD associated genes. The considerable significance of cluster analysis associated with gene network studies has led to reveal many disrupted key pathways in ASD, even if its genetic underpinnings remain a challenging task. This study aims to determine, through a novel data-driven approach, how networks of mutated genes impact biological processes underlying autism. Methods: We analyzed the VariCarta dataset, which presents more than 200,000 genomic variant events collected from 13,069 people with ASD. Firstly, we created a whole-genome and an exome sequencing subset. Then, for each subset we compared pairwise patients of each group to build “patient similarity matrices”. Hierarchical-agglomerative-clustering and heatmap were performed to identify clusters of patients with common occurrences of gene networks within these matrices. The subsequent enrichment analysis (EA) highlighted biological processes that might be impacted by the mutated genes of each subgroup. Results: Considering the whole-genome matrix, we identified three main genetic clusters of ASD patients, each one characterized by a network of shared genetic variants. We isolated 11,609 genetic variants shared by at least two subjects in each cluster; 4,187 of these variants (36.1%) were common to the three clusters. Only 331 patients (2.5%) shared none or very few mutated genes with anyone else. The EA highlighted common or cluster-specific biological processes related to the variants. Most of the common abnormal processes were involved in neuron projections guidance and morphogenesis, cell junctions and synapse assembly. Exome sequencing alone was not effectual in identifying ASD subgroups. Limitations: Caution is warranted when interpreting our results, as we did not compare them with a control group and did not verify if the identified subgroups where actually associated with different phenotypes. Future work will have to ascertain the strength and reproducibility of these results. Conclusions: Itemizing not just single mutated genes, but also gene networks and specific biological processes that characterize different ASD subpopulations might allow to better understand which networks of genetic variants play a major role in the etiopathology of ASD. The proposed methodology may represent a novel approach to help disentangle ASD complexity and an instrument to boost more focused genotype-phenotype studies.

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Section: Discussionmentioning

confidence: 99%

A novel data-driven approach reveals gene networks and biological processes underlying autism

Gialloreti¹,

Enea²,

Micco³

et al. 2020

Preprint

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“…Regulation of this turnover could be particularly affected in the neurodevelopmental disorders. It implicates that short-term multistep mechanisms underlying neuritogenesis, axon pathfinding, and dendritic spine motility, could be associated with autism spectrum disorders (Bakos et al 2015).…”

Section: Long-lasting Changes or Short-term Effects?mentioning

confidence: 99%

Neuronal morphology alterations in autism and possible role of oxytocin

Falougy

Filová

Ostatníková

et al. 2019

Endocrine Regulations

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Current understanding of the neuroanatomical abnormalities in autism includes gross anatomical changes in several brain areas and microstructural alterations in neuronal cells as well. There are many controversies in the interpretation of the imaging data, evaluation of volume and size of particular brain areas, and their functional translation into a broad autism phenotype. Critical questions of neuronal pathology in autism include the concept of the reversible plasticity of morphological changes, volume alterations of brain areas, and both short- and long-term consequences of adverse events present during the brain development. At the cellular level, remodeling of the actin cytoskeleton is considered as one of the critical factors associated with the autism spectrum disorders. Alterations in the composition of the neuronal cytoskeleton, in particular abnormalities in the polymerization of actin filaments and their associated proteins underlie the functional consequences in behavior resulting in symptoms and clinical correlates of autism spectrum disorder. In the present review, a special attention is devoted to the role of oxytocin in experimental models of neurodevelopmental disorders manifesting alterations in neuronal morphology.

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“…Although, it is still not fully understood, dysregulation of RhoA, Rac1, and Cdc42 may be a part of a mechanism involved in neurodevelopmental disorders. On the basis of analysis of publicly available microarray data, we have demonstrated a decreased expression of the Cdc42 in autistic subjects (Bakos, Bacova, Grant, Castejon, & Ostatnikova, ). Other bioinformatics data have shown that Cdc42 is a part of an interaction pathway associated with autism (Kalkan, Durasi, Sezerman, & Atasever‐Arslan, ).…”

Section: Alterations In Rho Gtpase‐mediated Pathways Contribute To Nementioning

confidence: 99%

Abnormalities in interactions of Rho GTPases with scaffolding proteins contribute to neurodevelopmental disorders

Reichova

Zatkova

Bačová

et al. 2017

J of Neuroscience Research

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Accumulating evidence suggests that Rho GTPases, together with scaffolding SHANK proteins, and associated signaling pathways play a role in the development of autism symptoms in various conditions. Research data have brought information on multiple intracellular signaling pathways, including Rho-associated protein kinases and serine/threonine-protein kinases involved in cytoskeleton rearranging. Alterations in downstream effectors of GTPase signaling pathways are associated with neurodevelopmental disorders. Bioinformatics and experimental data show that complex genetic and molecular defects (GTPases, actin-binding proteins, kinases, neuropeptides) can result in neuronal remodeling, leading to the functional connectivity deficits that manifest as the heterogeneous autism spectrum phenotype. Finally, the known hormone and neuropeptide oxytocin appears to be a factor for consideration in therapeutic intervention.

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Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis?

Cited by 56 publications

References 66 publications

A novel data-driven approach reveals gene networks and biological processes underlying autism

A novel data-driven approach reveals gene networks and biological processes underlying autism

Neuronal morphology alterations in autism and possible role of oxytocin

Abnormalities in interactions of Rho GTPases with scaffolding proteins contribute to neurodevelopmental disorders

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