Characterization of the proteome, diseases and evolution of the human postsynaptic density

Bayés, Àlex; Lagemaat, Louie N. van de; Collins, Mark O.; Croning, Mike D. R.; Whittle, Ian R.; Choudhary, Jyoti S.; Grant, Seth G. N.

doi:10.1038/nn.2719

Cited by 461 publications

(536 citation statements)

References 14 publications

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“…function, was downregulated in cerebral cortex from ASD subjects, in parallel with the observed decrease of the black module genes in TS observed here. Consistent with asdM12 annotation, the black module also was enriched for postsynaptic density (PSD) associated genes [68] (OR = 1.9, P = 0.001) that are critical regulators of synaptic signaling and plasticity. These observations suggest convergent synaptic dysfunction in this monogenic form of ASD caused by TS studied here and idiopathic ASD more broadly.…”

Section: Gene Co-expression Modules Dissect Pathways Related To Diffesupporting

confidence: 62%

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

et al. 2014

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Background: Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. To gain further mechanistic insights by extending previous gene expression data, we constructed co-expression networks in Timothy syndrome (TS), a monogenic condition with high penetrance for ASD, caused by mutations in the L-type calcium channel, Ca v 1.2. Methods: To identify patient-specific alterations in transcriptome organization, we conducted a genome-wide weighted co-expression network analysis (WGCNA) on neural progenitors and neurons from multiple lines of induced pluripotent stem cells (iPSC) derived from normal and TS (G406R in CACNA1C) individuals. We employed transcription factor binding site enrichment analysis to assess whether TS associated co-expression changes reflect calcium-dependent co-regulation.

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Section: Gene Co-expression Modules Dissect Pathways Related To Diffesupporting

confidence: 62%

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

et al. 2014

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“…Many of these proteins were unexpected and their functional significance in the PSD remains unknown. The total number of putative PSD proteins identified in various studies ranges from a few hundred to approximately 2000 (Jordan et al 2004;Li et al 2004;Peng et al 2004;Yoshimura et al 2004;Trinidad et al 2008;Bayes et al 2011). A common set of PSD proteins ( 460 proteins) has been deduced based on overlapping results from multiple proteomic studies (Collins et al 2006).…”

Section: Components Of the Psdmentioning

confidence: 99%

The Postsynaptic Organization of Synapses

Sheng¹,

Kim²

2011

Cold Spring Harbor Perspectives in Biology

475

426

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The postsynaptic side of the synapse is specialized to receive the neurotransmitter signal released from the presynaptic terminal and transduce it into electrical and biochemical changes in the postsynaptic cell. The cardinal functional components of the postsynaptic specialization of excitatory and inhibitory synapses are the ionotropic receptors (ligandgated channels) for glutamate and g-aminobutyric acid (GABA), respectively. These receptor channels are concentrated at the postsynaptic membrane and embedded in a dense and rich protein network comprised of anchoring and scaffolding molecules, signaling enzymes, cytoskeletal components, as well as other membrane proteins. Excitatory and inhibitory postsynaptic specializations are quite different in molecular organization. The postsynaptic density of excitatory synapses is especially complex and dynamic in composition and regulation; it contains hundreds of different proteins, many of which are required for cognitive function and implicated in psychiatric illness. E xcitatory synapses on principal neurons of mammalian brain occur mainly on tiny protrusions called dendritic spines (Bourne and Harris 2008). In contrast, inhibitory synapses are formed on the shaft of dendrites, or on cell bodies and axon initial segments. The postsynaptic side of excitatory synapses differs from inhibitory synapses not only in their content of neurotransmitter receptors but also in their morphology and molecular composition and organization. In part because of their greater abundance and distinctive structure, much more is known about the postsynaptic organization of central excitatory (glutamatergic) synapses. THE POSTSYNAPTIC DENSITY OF EXCITATORY SYNAPSESExcitatory synapses are characterized by a morphological and functional specialization of the postsynaptic membrane called the postsynaptic density (PSD), which is usually located at the tip of the dendritic spine. The PSD contains the glutamate receptors that are activated by the glutamate neurotransmitter released from the presynaptic terminal, as well as a host of associated signaling and structural molecules. A set of abundant scaffold proteins holds together the PSD by binding to the glutamate receptors, other postsynaptic receptors and adhesion

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“…Since molecular pathways underlying cognitive processes might be evolutionarily conserved 16,17,18 and indeed the rodent hippocampus has long been the primary model for studying molecular processes related to learning and memory 19 , we next aimed to identify which of the human hippocampus co-expression modules are preserved in the healthy mouse hippocampus. To this aim, we carried out high-throughput sequencing of mRNA (RNA-seq) on snap-frozen hippocampus samples from 100 healthy adult mice and assessed the co-expression patterns between the mouse orthologs of human hippocampus module genes (Methods).…”

Section: Table 2)mentioning

confidence: 99%

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

et al. 2015

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2Genetic determinants of cognition are poorly characterized and their relationship to genes that confer risk for neurodevelopmental disease is unclear. Here, we used a systems-level analysis of genome-wide gene expression data to infer gene-regulatory networks conserved across species and brain regions. Two of these networks, M1 and M3, showed replicable enrichment for common genetic variants underlying healthy human cognitive abilities including memory. Using exome sequence data from 6,871 trios, we find that M3 genes are also enriched for mutations ascertained from patients with neurodevelopmental disease generally, and intellectual disability and epileptic encephalopathy in particular. M3 consists of 150 genes whose expression is tightly developmentally regulated, but which are collectively poorly annotated for known functional pathways. These results illustrate how systems-level analyses can reveal previously unappreciated relationships between neurodevelopmental disease genes in the developed human brain, and provide empirical support for a convergent generegulatory network influencing cognition and neurodevelopmental disease.Cognition refers to human mental abilities such as memory, attention, processing speed, reasoning and executive function. Performance on cognitive tasks varies between individuals and is highly heritable 1 and polygenic 2,3 . However, to date, progress in identifying molecular genetic contributions to healthy human cognitive abilities has been limited 4,5 .A distinction can be made between cognitive domains such as the ability to apply acquired knowledge and learned skills (so called crystallized abilities) and fluid cognitive abilities such as the capacity to establish new memories, reason in novel situations or perform cognitive tasks accurately and quickly 6 . Notably, within individuals, performance on different measures of cognitive ability tend to be positively correlated such that people who do well in one domain, such as memory, tend to do well in other domains 7 . Seemingly disparate domains of cognitive ability also show high levels of genetic correlation in twin studies, typically in excess of 0.6 8 , and analyses using genome-wide similarity between unrelated individuals 3 (genome-wide complex trait analysis, GCTA) has also demonstrated substantial genetic correlation between diverse cognitive and learning abilities 9,10 . These studies suggest genes that influence human cognition may exert pleiotropic effects across diverse cognitive domains, such that genes regulating one cognitive ability might influence other cognitive abilities.Since impairment of cognitive function is a core clinical feature of many neurodevelopmental diseases including schizophrenia 11 , autism 12 , epilepsy 13 and intellectual disability (by definition), we sought to investigate gene-regulatory networks for human cognition and to determine their relationship to neurodevelopmental disease. An overview of our experimental design is provided in Supplementary Fig. 1. RESULTS Gene co-expression network a...

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Characterization of the proteome, diseases and evolution of the human postsynaptic density

Cited by 461 publications

References 14 publications

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome

The Postsynaptic Organization of Synapses

Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease

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