Cargando…

The ASD Living Biology: from cell proliferation to clinical phenotype

Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD beg...

Descripción completa

Detalles Bibliográficos
Autores principales: Courchesne, Eric, Pramparo, Tiziano, Gazestani, Vahid H., Lombardo, Michael V., Pierce, Karen, Lewis, Nathan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309606/
https://www.ncbi.nlm.nih.gov/pubmed/29934544
http://dx.doi.org/10.1038/s41380-018-0056-y
_version_ 1783383376910090240
author Courchesne, Eric
Pramparo, Tiziano
Gazestani, Vahid H.
Lombardo, Michael V.
Pierce, Karen
Lewis, Nathan E.
author_facet Courchesne, Eric
Pramparo, Tiziano
Gazestani, Vahid H.
Lombardo, Michael V.
Pierce, Karen
Lewis, Nathan E.
author_sort Courchesne, Eric
collection PubMed
description Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child’s development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD.
format Online
Article
Text
id pubmed-6309606
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-63096062019-02-02 The ASD Living Biology: from cell proliferation to clinical phenotype Courchesne, Eric Pramparo, Tiziano Gazestani, Vahid H. Lombardo, Michael V. Pierce, Karen Lewis, Nathan E. Mol Psychiatry Expert Review Autism spectrum disorder (ASD) has captured the attention of scientists, clinicians and the lay public because of its uncertain origins and striking and unexplained clinical heterogeneity. Here we review genetic, genomic, cellular, postmortem, animal model, and cell model evidence that shows ASD begins in the womb. This evidence leads to a new theory that ASD is a multistage, progressive disorder of brain development, spanning nearly all of prenatal life. ASD can begin as early as the 1st and 2nd trimester with disruption of cell proliferation and differentiation. It continues with disruption of neural migration, laminar disorganization, altered neuron maturation and neurite outgrowth, disruption of synaptogenesis and reduced neural network functioning. Among the most commonly reported high-confidence ASD (hcASD) genes, 94% express during prenatal life and affect these fetal processes in neocortex, amygdala, hippocampus, striatum and cerebellum. A majority of hcASD genes are pleiotropic, and affect proliferation/differentiation and/or synapse development. Proliferation and subsequent fetal stages can also be disrupted by maternal immune activation in the 1st trimester. Commonly implicated pathways, PI3K/AKT and RAS/ERK, are also pleiotropic and affect multiple fetal processes from proliferation through synapse and neural functional development. In different ASD individuals, variation in how and when these pleiotropic pathways are dysregulated, will lead to different, even opposing effects, producing prenatal as well as later neural and clinical heterogeneity. Thus, the pathogenesis of ASD is not set at one point in time and does not reside in one process, but rather is a cascade of prenatal pathogenic processes in the vast majority of ASD toddlers. Despite this new knowledge and theory that ASD biology begins in the womb, current research methods have not provided individualized information: What are the fetal processes and early-age molecular and cellular differences that underlie ASD in each individual child? Without such individualized knowledge, rapid advances in biological-based diagnostic, prognostic, and precision medicine treatments cannot occur. Missing, therefore, is what we call ASD Living Biology. This is a conceptual and paradigm shift towards a focus on the abnormal prenatal processes underlying ASD within each living individual. The concept emphasizes the specific need for foundational knowledge of a living child’s development from abnormal prenatal beginnings to early clinical stages. The ASD Living Biology paradigm seeks this knowledge by linking genetic and in vitro prenatal molecular, cellular and neural measurements with in vivo post-natal molecular, neural and clinical presentation and progression in each ASD child. We review the first such study, which confirms the multistage fetal nature of ASD and provides the first in vitro fetal-stage explanation for in vivo early brain overgrowth. Within-child ASD Living Biology is a novel research concept we coin here that advocates the integration of in vitro prenatal and in vivo early post-natal information to generate individualized and group-level explanations, clinically useful prognoses, and precision medicine approaches that are truly beneficial for the individual infant and toddler with ASD. Nature Publishing Group UK 2018-06-22 2019 /pmc/articles/PMC6309606/ /pubmed/29934544 http://dx.doi.org/10.1038/s41380-018-0056-y Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Expert Review
Courchesne, Eric
Pramparo, Tiziano
Gazestani, Vahid H.
Lombardo, Michael V.
Pierce, Karen
Lewis, Nathan E.
The ASD Living Biology: from cell proliferation to clinical phenotype
title The ASD Living Biology: from cell proliferation to clinical phenotype
title_full The ASD Living Biology: from cell proliferation to clinical phenotype
title_fullStr The ASD Living Biology: from cell proliferation to clinical phenotype
title_full_unstemmed The ASD Living Biology: from cell proliferation to clinical phenotype
title_short The ASD Living Biology: from cell proliferation to clinical phenotype
title_sort asd living biology: from cell proliferation to clinical phenotype
topic Expert Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6309606/
https://www.ncbi.nlm.nih.gov/pubmed/29934544
http://dx.doi.org/10.1038/s41380-018-0056-y
work_keys_str_mv AT courchesneeric theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT pramparotiziano theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT gazestanivahidh theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT lombardomichaelv theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT piercekaren theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT lewisnathane theasdlivingbiologyfromcellproliferationtoclinicalphenotype
AT courchesneeric asdlivingbiologyfromcellproliferationtoclinicalphenotype
AT pramparotiziano asdlivingbiologyfromcellproliferationtoclinicalphenotype
AT gazestanivahidh asdlivingbiologyfromcellproliferationtoclinicalphenotype
AT lombardomichaelv asdlivingbiologyfromcellproliferationtoclinicalphenotype
AT piercekaren asdlivingbiologyfromcellproliferationtoclinicalphenotype
AT lewisnathane asdlivingbiologyfromcellproliferationtoclinicalphenotype