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.

mGluR5 Regulates Glutamate-Dependent Development of the Mouse Somatosensory Cortex

“…5, 6) (Datwani et al, 2002;Inan et al, 2006). Nonetheless, it is clear that the role that glutamate plays in the establishment of cortical connectivity and plasticity is crucial to normal cognitive development as the genes encoding several PSD proteins are mutated in various cognitive disorders (Tarpey et al, 2004;Grant et al, 2005). Dissecting specific cellular processes regulated by different components of the PSD will be important for understanding the etiology of the diseases they underlie.…”

Altered expression of synaptic protein mRNAs in STOP (MAP6) mutant mice

“…As such, synaptic pathology in schizophrenia may have its origin elsewhere in the neuron (or even in non-neuronal cells). This is particularly relevant to our understanding of how susceptibility genes for schizophrenia may converge to alter synaptic function, given that most do not encode established structural components of the synapse or proteins known to be part of the synaptic proteome (see Grant et al, 2005;Harrison and Weinberger, 2005). Of note, one of the leading susceptibility genes, DISC1 (Disrupted in Schizophrenia 1), forms a complex with several proteins including NUDEL (nuclear distribution element-like) and Lis1 (lissencephaly gene 1 product), which binds to microtubules and is involved in neuronal migration and dynein-mediated motor transport (see Brandon et al, 2004;Kamiya et al, 2005.).…”

Neuroproteomics – the tasks lying ahead

“…Third, PTMs of proteins can be identified and characterized [116,117]. Fourth, multiprotein complexes take center-stage concerning our understanding of physiological and pathophysiological processes [118,119].…”

“…The comprehensive identification and characterization of protein complexes is hence a prerequisite for improved understanding of regulatory and signaling mechanisms in neurotransmission. Furthermore, this analysis will break new grounds for polygenic disease traits, by identifying sets of genes with a functional link [118]. An in-depth investigation of the NMDA receptor complex identified 185 proteins.…”

“…An in-depth investigation of the NMDA receptor complex identified 185 proteins. Forty-seven of the corresponding genes were associated with nervous system disorders such as autism and schizophrenia [84,118,143]. However, the actual composition of the NMDA receptor in different neuron types is unknown and likely subject to changes.…”