MASC complexes and the genetics of human cognition
At excitatory synapses in the central nervous system neurotransmitter receptors are components of multiprotein complexes containing dozens of proteins embedded in the post synaptic density. A prototype synaptic complex defined by proteomic experiments comprises 185 proteins in the N-methyl-D-aspartate receptor complex/MAGUK Associated Signalling Complex (NRC/MASC) (Husi et al, 2000; Collins et al, 2005). Mutations or polymorphisms in 47 genes have been reported and associated with 183 disorders, of which 54 were nervous system disorders (Grant et al, 2005). A similar number of genes are important in mouse synaptic plasticity and behaviour. We have previously shown that this set of proteins has a network topology that predicts features of robustness and complexity (Pocklington et al, 2006). These data support the model that synapse complexes are targets for disease (complexopathies) and regulate normal behavioural plasticity.
Collins MO, Husi H, Yu L, Brandon JM, Anderson CN, Blackstock WP, Choudhary JS, Grant SG. Molecular characterization and comparison of the components and multiprotein complexes in the postsynaptic proteome. J Neurochem. 2005
Grant SG, Marshall MC, Page KL, Cumiskey MA, Armstrong JD. Synapse proteomics of multiprotein complexes: en route from genes to nervous system diseases. Hum Mol Genet. 2005 Oct 15;14 Spec No. 2:R225-34. Epub 2005 Sep 8.
Husi H., Ward M.A., Choudhary J.S., Blackstock W.P., Grant S.G. Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. Nature Neuroscience 2000.
Pocklington, A.J., Cumiskey, M., Armstrong, J.D.A., Grant, S.G.N. The proteomes of neurotransmitter receptor complexes form modular networks with distributed functionality underlying plasticity and behaviour. Molecular Systems Biology. Published online: 17 January 2006