Proteomic analysis of postsynaptic proteins in regions of the human neocortex

Roy, Marcia; Sorokina, Oksana; Skene, Nathan G.; Simonnet, Clémence; Mazzo, Francesca; Zwart, Ruud; Sher, Emanuele; Smith, Colin; Armstrong, J. Douglas; Grant, Seth G. N.

doi:10.1038/s41593-017-0025-9

Cited by 70 publications

(87 citation statements)

References 62 publications

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“…Synapses are also highly complex at the molecular level, with >1,000 genes encoding postsynaptic proteins in excitatory synapses (Bayés et al., 2011, Bayés et al., 2012, Bayés et al., 2017, Collins et al., 2006, Distler et al., 2014, Emes et al., 2008, Husi et al., 2000, Peng et al., 2004, Roy et al., 2018, Trinidad et al., 2008, Uezu et al., 2016, Yoshimura et al., 2004). The differential expression of these proteins raises the possibility that there is high synapse diversity within the brain (Grant, 2007, Emes et al., 2008, O’Rourke et al., 2012).…”

Section: Introductionmentioning

confidence: 99%

Architecture of the Mouse Brain Synaptome

Zhu

Cizeron

Qiu

et al. 2018

Neuron

196

359

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SummarySynapses are found in vast numbers in the brain and contain complex proteomes. We developed genetic labeling and imaging methods to examine synaptic proteins in individual excitatory synapses across all regions of the mouse brain. Synapse catalogs were generated from the molecular and morphological features of a billion synapses. Each synapse subtype showed a unique anatomical distribution, and each brain region showed a distinct signature of synapse subtypes. Whole-brain synaptome cartography revealed spatial architecture from dendritic to global systems levels and previously unknown anatomical features. Synaptome mapping of circuits showed correspondence between synapse diversity and structural and functional connectomes. Behaviorally relevant patterns of neuronal activity trigger spatiotemporal postsynaptic responses sensitive to the structure of synaptome maps. Areas controlling higher cognitive function contain the greatest synapse diversity, and mutations causing cognitive disorders reorganized synaptome maps. Synaptome technology and resources have wide-ranging application in studies of the normal and diseased brain.

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Section: Introductionmentioning

confidence: 99%

Architecture of the Mouse Brain Synaptome

Zhu

Cizeron

Qiu

et al. 2018

Neuron

196

359

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“…Over the past two decades, proteomic studies have revealed remarkable synapse complexity and diversity. In these studies, biochemically purified protein complexes from the postsynaptic density were analysed and found to contain over 1,000 different protein components (Bayes et al, 2012(Bayes et al, , 2017(Bayes et al, , 2011Collins et al, 2006;Distler et al, 2014;Emes et al, 2008;Grant, 2007;Peng et al, 2004;Roy et al, 2018;Trinidad, Specht, Thalhammer, Schoepfer, & Burlingame, 2006;Trinidad et al, 2008;Uezu et al, 2016). The functional diversification of synapses is often related to their molecular diversity.…”

Section: Introductionmentioning

confidence: 99%

“…The functional diversification of synapses is often related to their molecular diversity. It has been reported that many synaptic proteins, including different subtypes of receptors, isoforms of scaffolding proteins and adhesion molecules, are differentially expressed in various brain regions (Bayes et al, 2012(Bayes et al, , 2011Collins et al, 2006;Emes et al, 2008;Frank et al, 2016;Frank, Zhu, Komiyama, & Grant, 2017;Husi, Ward, Choudhary, Blackstock, & Grant, 2000;Komiyama et al, 2002;Lein et al, 2007;Micheva, Busse, Weiler, O'Rourke, & Smith, 2010;Roy et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Cell‐type‐specific visualisation and biochemical isolation of endogenous synaptic proteins in mice

Zhu

Collins

Harmse

et al. 2019

Eur J of Neuroscience

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In recent years, the remarkable molecular complexity of synapses has been revealed, with over 1,000 proteins identified in the synapse proteome. Although it is known that different receptors and other synaptic proteins are present in different types of neurons, the extent of synapse diversity across the brain is largely unknown. This is mainly due to the limitations of current techniques. Here, we report an efficient method for the purification of synaptic protein complexes, fusing a high‐affinity tag to endogenous PSD95 in specific cell types. We also developed a strategy, which enables the visualisation of endogenous PSD95 with fluorescent‐protein tag in Cre‐recombinase‐expressing cells. We demonstrate the feasibility of proteomic analysis of synaptic protein complexes and visualisation of these in specific cell types. We find that the composition of PSD95 complexes purified from specific cell types differs from those extracted from tissues with diverse cellular composition. The results suggest that there might be differential interactions in the PSD95 complexes in different brain regions. We have detected differentially interacting proteins by comparing data sets from the whole hippocampus and the CA3 subfield of the hippocampus. Therefore, these novel conditional PSD95 tagging lines will not only serve as powerful tools for precisely dissecting synapse diversity in specific brain regions and subsets of neuronal cells, but also provide an opportunity to better understand brain region‐ and cell‐type‐specific alterations associated with various psychiatric/neurological diseases. These newly developed conditional gene tagging methods can be applied to many different synaptic proteins and will facilitate research on the molecular complexity of synapses.

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“…Studies of mutations implicated in neurodevelopmental disorders specifically led to the “synaptic hypothesis” that neurodevelopmental disorders result from impaired assembly and/or maintenance of synapses (Gigek et al., ). Elongation factors have certainly been shown to be key in the lasting potentiation of synapses (Giustetto et al., ; Roy et al., ). Both isoforms of eEF1A have been reported to be present at synapses and to have a role in clustering of gephyrin, a scaffold protein involved in anchoring receptor molecules to postsynaptic membranes (Becker, Kuhse, & Kirsch, ).…”

Section: Why Do Mutations In Genes With Housekeeping Functions Lead Tmentioning

confidence: 99%

The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders

2018

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The multi‐subunit eEF1 complex plays a crucial role in de novo protein synthesis. The central functional component of the complex is eEF1A, which occurs as two independently encoded variants with reciprocal expression patterns: whilst eEF1A1 is widely expressed, eEF1A2 is found only in neurons and muscle. Heterozygous mutations in the gene encoding eEF1A2, EEF1A2, have recently been shown to cause epilepsy, autism, and intellectual disability. The remaining subunits of the eEF1 complex, eEF1Bα, eEF1Bδ, eEF1Bγ, and valyl‐tRNA synthetase (VARS), together form the GTP exchange factor for eEF1A and are ubiquitously expressed, in keeping with their housekeeping role. However, mutations in the genes encoding these subunits EEF1B2 (eEF1Bα), EEF1D (eEF1Bδ), and VARS (valyl‐tRNA synthetase) have also now been identified as causes of neurodevelopmental disorders. In this review, we describe the mutations identified so far in comparison with the degree of normal variation in each gene, and the predicted consequences of the mutations on the functions of the proteins and their isoforms. We discuss the likely effects of the mutations in the context of the role of protein synthesis in neuronal development.

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Proteomic analysis of postsynaptic proteins in regions of the human neocortex

Cited by 70 publications

References 62 publications

Architecture of the Mouse Brain Synaptome

Architecture of the Mouse Brain Synaptome

Cell‐type‐specific visualisation and biochemical isolation of endogenous synaptic proteins in mice

The role of translation elongation factor eEF1 subunits in neurodevelopmental disorders

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