Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases
Abstract
Proteomic experiments have produced a draft profile of the overall molecular composition of the mammalian neuronal synapse. It appears that synapses have over 1000 protein components and the mapping of their interactions, organization and functions will lead to a global view of the role of synapses in physiology and disease. A major functional subcomponent of the synaptic machinery is a multiprotein complex of glutamate receptors and adhesion proteins with associated adaptor and signalling enzymes totally 185 proteins known as the N-methyl-d-aspartate receptor complex/MAGUK associated signalling complex (NRC/MASC). Here, we review the proteomic studies and functions of NRC/MASC and specifically report on the role of its component genes in human diseases. Using a systematic literature search protocol, we identified reports of mutations or polymorphisms in 47 genes associated with 183 disorders, of which 54 were nervous system disorders. A similar number of genes are important in mouse synaptic plasticity and behaviour, where the NRC/MASC acts as a signalling complex with multiple functions provided by its individual protein components and their interactions. The individual gene mutations suggest not only an important role for the NRC/MASC in human diseases but that these diseases may be functionally connected by their common link to the NRC/MASC. The NRC/MASC is a rich source of genetic variation and provides a platform for understanding relationships of disease phenotype amenable to systematic studies such as the Genes to Cognition research consortium (www.genes2cognition.org) that links human and mouse genetics with proteomic studies.
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Disruption of a number of synaptic proteins linked to glutamate receptor signalling alters cognitive function in rodents.
“It is clear that disruption of a number of synaptic proteins linked to glutamate receptor signalling alters cognitive function in rodents.44”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [44]
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- Authors
- Grant, S. G. N., Marshall, M. C., Page, K.-L., Cumiskey, M. A., & Armstrong, J. D.
- Affiliations
- Wellcome Sanger Institute (GB)
- Corresponding author
- Grant, Seth G.N.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-10-15
- Volume
- 14
- Issue
- suppl_2
- Pages
- R225-R234
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2131679574
- Cited by
- 64
- References
- 16
- Citations by year
- 2021: 1 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 1 · 2014: 3 · 2013: 1 · 2012: 5
- FWCI
- 2.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- glutamate receptors, synaptic adhesion proteins, genetic mutations, genetic polymorphism, neurological disorders, synaptic plasticity, mouse behavior
- MeSH terms
- Humans, Mutation, Nervous System Diseases, Polymorphism, Genetic, Synapses, Receptors, N-Methyl-D-Aspartate, Receptors, Glutamate, Proteomics, Macromolecular Substances, Multiprotein Complexes, Intracellular Signaling Peptides and Proteins
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