Abstract
Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons—which has an expression profile more closely related to fetal brain—while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target.
Highlights
It has been long recognized that genetic factors play an important role in autism spectrum disorder (ASD) [1, 2], a neurodevelopmental disorder characterized by impairments in social-communicative skills and repetitive behaviors, that affects at least 1% of the population [3, 4]
Some studies using Induced pluripotent stem cell (iPSC)-derived neuronal cells have explored transcriptome profiles of relatively small samples of idiopathic ASD individuals, including two studies that have selected only macrocephalic patients [16, 17], who represent less than 20% of the ASD patients [18], and a study on a sample enriched with low-functioning normocephalic patients [19]
Considering the genetic and phenotypic heterogeneity of the disease, further studies are needed to increase the number of examined patients, specially to investigate other ASD endophenotypes, and to clarify the correlation between the results found in postmortem brain tissue and those found using in vitro neuronal models
Summary
It has been long recognized that genetic factors play an important role in autism spectrum disorder (ASD) [1, 2], a neurodevelopmental disorder characterized by impairments in social-communicative skills and repetitive behaviors, that affects at least 1% of the population [3, 4]. Despite the large number of ASD-candidate genes described so far, they seem to converge on a few final common effectors or molecular pathways [6], suggesting that the different genetic variants associated with the disease may lead to similar functional consequences, which might be reflected in the transcriptional level, protein level or, lately, in the regulation of specific cellular mechanisms Based on this premise, whole transcriptome studies have been conducted to explore differentially expressed gene profiles associated with ASD, mainly using postmortem brain tissue from autistic individuals [7,8,9,10]. Considering the genetic and phenotypic heterogeneity of the disease, further studies are needed to increase the number of examined patients, specially to investigate other ASD endophenotypes, and to clarify the correlation between the results found in postmortem brain tissue and those found using in vitro neuronal models
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