Proteomic Investigations of Autism Spectrum Disorder: Past Findings, Current Challenges, and Future Prospects

Abraham, Joseph R; Szoko, Nicholas; Natowicz, Marvin R.

doi:10.1007/978-3-030-05542-4_12

Cited by 23 publications

(21 citation statements)

References 85 publications

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“…However, the mechanisms associated with these proteins such as inflammation, protein misfolding and alteration of mitochondrial activity are presumably common responses to many internal and external challenges, thereby affecting their specificity as a diagnostic marker. Nevertheless, very recently, two review studies on autism proteomics and biomarkers highlighted the close relationship between these mechanisms and ASD (Abraham et al, 2019 ; Shen et al, 2019 ). They may be interacted with each other, and related to the occurrence and development of these diseases, and may be primary or secondary phenomena (Abraham et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

“…Nevertheless, very recently, two review studies on autism proteomics and biomarkers highlighted the close relationship between these mechanisms and ASD (Abraham et al, 2019 ; Shen et al, 2019 ). They may be interacted with each other, and related to the occurrence and development of these diseases, and may be primary or secondary phenomena (Abraham et al, 2019 ). Given the complexity of ASD pathogenesis, a panel of proteins rather than a single protein could be a more powerful approach to diagnose this disease.…”

Section: Discussionmentioning

confidence: 99%

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Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Shen

Feng

Zhang

et al. 2019

Front. Cell. Neurosci.

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Autism is one of the most common neurological developmental disorder associated with social isolation and restricted interests in children. The etiology of this disorder is still unknown. There is neither any confirmed laboratory test nor any effective therapeutic strategy to diagnose or cure it. To search for biomarkers for early detection and exploration of the disease mechanisms, here, we investigated the protein expression signatures of peripheral blood mononuclear cells (PBMCs) in autistic children compared with healthy controls by using isobaric tags for relative and absolute quantitation (iTRAQ) proteomics approach. The results showed a total of 41 proteins as differentially expressed in autistic group as compared to control. These proteins are found associated with metabolic pathways, endoplasmic reticulum (ER) stress and protein folding, endocytosis, immune and inflammatory response, plasma lipoprotein particle organization, and cell adhesion. Among these, 17 proteins (13 up-regulated and four down-regulated) are found to be linked with mitochondria. Eight proteins including three already reported proteins in our previous studies were selected to be verified. Five already reported autism associated pro-inflammatory cytokines [interferon-γ (IFN-γ), interleukin-1β (IL-1β), IL-6, IL-12, and tumor necrosis factor-α (TNF-α)] were detected in plasma by enzyme-linked immunosorbent assay (ELISA) analysis. The results were consistent with proteomic results and reports from previous literature. These results proposed that PBMCs from autistic children might be activated, and ER stress, unfolded protein response (UPR), acute-phase response (APR), inflammatory response, and endocytosis may be involved in autism occurrence. These reported proteins may serve as potential biomarkers for early diagnosis of autism. More specifically, simultaneous detection of three proteins [complement C3 (C3), calreticulin (CALR), and SERPINA1] in the plasma and PBMCs could increase the authenticity of detection.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Shen

Feng

Zhang

et al. 2019

Front. Cell. Neurosci.

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“…Despite the power of proteomics and its increasing utilization in the understanding of neurological and developmental disorders, there are few applications of proteomic approaches to the study of ASD 24,25 . Moreover, most of the proteomic studies of ASD have examined non-neural tissue and no consistent findings have been apparent 25 .…”

Section: Introductionmentioning

confidence: 99%

Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes

Abraham

Szoko

Barnard

et al. 2019

Sci Rep

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Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions defined by impairments in social communication and restricted, repetitive behaviors, interests or activities. Only a minority of ASD cases are determined to have a definitive etiology and the pathogenesis of most ASD is poorly understood. We hypothesized that a global analysis of the proteomes of human ASD vs. control brain, heretofore not done, would provide important data with which to better understand the underlying neurobiology of autism. In this study, we characterized the proteomes of two brain regions, Brodmann area 19 (BA19) and posterior inferior cerebellum (CB), from carefully selected idiopathic ASD cases and matched controls using label-free HPLC-tandem mass spectrometry. The data revealed marked differences between ASD and control brain proteomes for both brain regions. Unlike earlier transcriptomic analyses using frontal and temporal cortex, however, our proteomic analysis did not support ASD attenuating regional gene expression differences. Bioinformatic analyses of the differentially expressed proteins between cases and controls highlighted canonical pathways involving glutamate receptor signaling and glutathione-mediated detoxification in both BA19 and CB; other pathways such as Sertoli cell signaling and fatty acid oxidation were specifically enriched in BA19 or CB, respectively. Network analysis of both regions of ASD brain showed up-regulation of multiple pre- and post-synaptic membrane or scaffolding proteins including glutamatergic ion channels and related proteins, up-regulation of proteins involved in intracellular calcium signaling, and down-regulation of neurofilament proteins, with DLG4 and MAPT as major hub proteins in BA19 and CB protein interaction networks, respectively. Upstream regulator analysis suggests neurodegeneration-associated proteins drive the differential protein expression for ASD in both BA19 and CB. Overall, the proteomic data provide support for shared dysregulated pathways and upstream regulators for two brain regions in human ASD brain, suggesting a common ASD pathophysiology that has distinctive regional expression.

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“…Next-Generation Sequencing (NGS) technology has gifted biomedical science a tool for exploration of big data, especially for complex diseases like ASD. While there have been several rigorous efforts to explore the transcriptome of ASD [7][8][9][10][11][12][13][14], there has been a limited exploration of the proteome of ASD [15][16][17][18][19]. Little has been done to understand the proteome, let alone characterize the functional effectors of the phosphoproteome in syndromic ASD contexts, such as those arising from Mendelian gene variation, here, germline PTEN mutation.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome-(Phospho)proteome Characterization of the Brain of a Constitutional Model of Cytoplasmic-predominant Pten Expression With Autism-Like Phenotypes

Thacker

Eng

2020

Preprint

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BackgroundPTEN, a well-studied tumor suppressor, has one of the strongest Mendelian associations with autism spectrum disorder (ASD), representing a special case in autism’s complex genetic architecture. Animal modeling for constitutional Pten mutation creates an opportunity to study how disruption of Pten affects neurobiology, providing insights that may be generalizable or at least inform our understanding of ASD. Although the neural transcriptome has been well characterized in Pten models, little has been done concerning the proteome and phosphoproteome. This is a critical gap in knowledge given that these –omic landscapes are more proximal to the actively observed biology than the transcriptome.MethodsWe sought to comprehensively characterize the neural proteome and phosphoproteome of the Ptenm3m4/m3m4 mouse, which exhibits cytoplasmic-predominant Pten expression. Proteomic and phosphoproteomic scans of Ptenm3m4/m3m4 and wildtype mouse brain at two-weeks- (P14) and six-weeks-of-age (P40) were performed using liquid chromatography with tandem mass spectrometry technology. Following quantification of differentially expressed/phosphorylated proteins, we performed gene overlap, gene enrichment, pathway, and network analyses to identify the similarity across the various datasets and understand the affected biological landscape.ResultsWe identified numerous differentially expressed/phosphorylated proteins, finding that dysregulation was greater at P40, consistent with the prior neural transcriptome data. We found the affected biological pathways were largely related to PTEN function, neurological processes, or neuroinflammation. Although we found minimal overlap among differentially expressed transcriptome-proteome-phosphoproteome molecules between P14 and P40 brains, there was congruence amongst the affected pathways. Importantly, network analysis identified Pten and Psd-95 as predominant regulatory nodes in the proteome and phosphoproteome, respectively. Moreover, we found overlap between our differentially expressed/phosphorylated proteins and known ASD risk genes.ConclusionsDifferential expression/phosphorylation revealed by transcriptome-proteome/phosphoproteome analyses of a germline Pten mutation model point to ASD risk genes like Pten and Psd-95 as major hubs in the protein networks, highlighting their important regulatory influence. Our observations here suggest Pten and Psd-95, known interactors in biological networks in the brain, are critical to either initiation or maintenance of cellular and perhaps organismal phenotypes related to ASD. Future research should explore rescuing Pten and Psd-95 function in attempts to ameliorate neurological pathologies and behavioral abnormalities.

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Proteomic Investigations of Autism Spectrum Disorder: Past Findings, Current Challenges, and Future Prospects

Cited by 23 publications

References 85 publications

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Proteomics Study of Peripheral Blood Mononuclear Cells (PBMCs) in Autistic Children

Proteomic Investigations of Autism Brain Identify Known and Novel Pathogenetic Processes

Transcriptome-(Phospho)proteome Characterization of the Brain of a Constitutional Model of Cytoplasmic-predominant Pten Expression With Autism-Like Phenotypes

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