Article

Synaptopathies: diseases of the synaptome

Genes to Cognition Programme, Centre for Clinical Brain Sciences, The University of Edinburgh, Chancellors Building, 47 Little France Crescent, Edinburgh EH16 4SB, United Kingdom.
Current opinion in neurobiology (Impact Factor: 6.77). 03/2012; 22(3):522-9. DOI: 10.1016/j.conb.2012.02.002
Source: PubMed

ABSTRACT The human synapse proteome is a highly complex collection of proteins that is disrupted by hundreds of gene mutations causing over 100 brain diseases. These synaptic diseases, or synaptopathies, cause major psychiatric, neurological and childhood developmental disorders through mendelian and complex genetic mechanisms. The human postsynaptic proteome and its core signaling complexes built by the assembly of receptors and enzymes around Membrane Associated Guanylate Kinase (MAGUK) scaffold proteins are a paradigm for systematic analysis of synaptic diseases. In humans, the MAGUK Associated Signaling Complexes are mutated in Autism, Schizophrenia, Intellectual Disability and many other diseases, and mice carrying orthologous mutations show relevant cognitive, social, motoric and other phenotypes. Diseases with similar phenotypes and symptom spectrums arise from disruption of complexes and interacting proteins within the synapse proteome. Classifying synaptic disease phenotypes with genetic and proteome data provides a new brain disease classification system based on molecular etiology and pathogenesis.

3 Followers
 · 
278 Views
  • Source
    • "Proper formation and function of synapses require the coordinated assembly of large and heterogeneous protein complexes on the pre-and postsynaptic side. The composition of the synaptic proteome varies with synaptic neurotransmitter type and developmental stage, changes upon activity-induced changes in synaptic strength, and is affected in synaptopathies (Cajigas et al., 2010; Grant, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The formation, function, and plasticity of synapses require dynamic changes in synaptic receptor composition. Here, we identify the sorting receptor SorCS1 as a key regulator of synaptic receptor trafficking. Four independent proteomic analyses identify the synaptic adhesion molecule neurexin and the AMPA glutamate receptor (AMPAR) as major proteins sorted by SorCS1. SorCS1 localizes to early and recycling endosomes and regulates neurexin and AMPAR surface trafficking. Surface proteome analysis of SorCS1-deficient neurons shows decreased surface levels of these, and additional, receptors. Quantitative in vivo analysis of SorCS1-knockout synaptic proteomes identifies SorCS1 as a global trafficking regulator and reveals decreased levels of receptors regulating adhesion and neurotransmission, including neurexins and AMPARs. Consequently, glutamatergic transmission at SorCS1-deficient synapses is reduced due to impaired AMPAR surface expression. SORCS1 mutations have been associated with autism and Alzheimer disease, suggesting that perturbed receptor trafficking contributes to synaptic-composition and -function defects underlying synaptopathies. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neuron 08/2015; 87(4):764-80. DOI:10.1016/j.neuron.2015.08.007 · 15.98 Impact Factor
  • Source
    • "DLGAP2 (also known as SAPAP2 or GKAP2), as one of the main components of postsynaptic scaffolding proteins, directly interacts with DLG4 (also known as PSD-95) and SHANKs to form the DLG4-DLGAPs-SHANKs complex, which plays critical roles in synaptic morphogenesis and functions [12-14]. Human genetic studies point out that mutations of synaptic scaffold proteins may contribute to the etiology of psychiatric and neurodevelopmental disorders [15,16]. Further, DLG4[17], SHANKs[18-20] and DLGAP2[8,21,22] have been listed as possible candidate genes for autism. "
    [Show abstract] [Hide abstract]
    ABSTRACT: As elegant structures designed for neural communication, synapses are the building bricks of our mental functions. Recently, many studies have pointed out that synaptic protein-associated mutations may lead to dysfunctions of social cognition. Dlgap2, which encodes one of the main components of scaffold proteins in postsynaptic density (PSD), has been addressed as a candidate gene in autism spectrum disorders. To elucidate the disturbance of synaptic balance arising from Dlgap2 loss-of-function in vivo, we thus generated Dlgap2 (-/-) mice to investigate their phenotypes of synaptic function and social behaviors.
    Molecular Autism 05/2014; 5:32. DOI:10.1186/2040-2392-5-32 · 5.49 Impact Factor
  • Source
    • "An ideal understanding of brain computation and function will also require insights at the synaptic level. Perturbations at this level as seen with Schizophrenia, Fragile X syndrome, and Rett syndrome highlight the need to understand what constitutes normal brain connectivity (Chahrour and Zoghbi, 2007; Lauriat and Mcinnes, 2007; Featherstone, 2010; Toro et al., 2010; Auerbach et al., 2011; Grant, 2012). Zebrafish allow a large shift in scale, from whole brain to neural network down to subsynaptic components. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Recent advances in imaging tools are inspiring zebrafish researchers to tackle ever more ambitious questions in the neurosciences. Behaviorally fundamental conserved neural networks can now be potentially studied using zebrafish from a brain-wide scale to molecular resolution. In this perspective, we offer a roadmap by which a zebrafish researcher can navigate the course from collecting neural activities across the brain associated with a behavior, to unraveling molecular identities and testing the functional relevance of active neurons. In doing so, important insights will be gained as to how neural networks generate behaviors and assimilate changes in synaptic connectivity.
    Frontiers in Neural Circuits 04/2013; 7:76. DOI:10.3389/fncir.2013.00076 · 2.95 Impact Factor
Show more