Abstract
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.
Highlights
More than 100 mendelian and cytogenomic variants have been causally associated with Autism Spectrum Disorder (ASD), all of which are uncommon or rare and many of which are incompletely characterized[9,10,11]; environmental factors, while clearly relevant, are even less well understood[12]
Diverse investigative approaches - from neuropathological evaluation to functional neuroimaging - suggest that persons with ASD have central nervous system (CNS) developmental dysconnectivity, and important theories of ASD pathogenesis center on abnormal synaptic homeostasis and the abnormal development or regulation of neuronal circuitry[14,15,16]
The proteomic analysis of ASD and control samples detected 9205 peptides belonging to 1807 proteins in Brodmann area 19 (BA19) occipital cortex and 8017 peptides from 1640 proteins in cerebellar (CB) tissue
Summary
More than 100 mendelian and cytogenomic variants have been causally associated with ASD, all of which are uncommon or rare and many of which are incompletely characterized[9,10,11]; environmental factors, while clearly relevant, are even less well understood[12]. At this time, despite extensive diagnostic evaluation, the vast majority of persons with ASD do not receive an etiological diagnosis and receive a diagnosis of autism of unknown etiology www.nature.com/scientificreports/. Most of the proteomic studies of ASD have examined non-neural tissue and no consistent findings have been apparent[25]
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