The role of neuronal complexes in human X-linked brain diseases

Abstract

Beyond finding individual genes that are involved in medical disorders, an important challenge is the integration of sets of disease genes with the complexities of basic biological processes. We examine this issue by focusing on neuronal multiprotein complexes and their components encoded on the human X chromosome. Multiprotein signaling complexes in the postsynaptic terminal of central nervous system synapses are essential for the induction of neuronal plasticity and cognitive processes in animals. The prototype complex is the N-methyl-D-aspartate receptor complex/membrane-associated guanylate kinase-associated signaling complex (NRC/MASC) comprising 185 proteins and embedded within the postsynaptic density (PSD), which is a set of complexes totaling approximately 1,100 proteins. It is striking that 86% (6 of 7) of X-linked NRC/MASC genes and 49% (19 of 39) of X-chromosomal PSD genes are already known to be involved in human psychiatric disorders. Moreover, of the 69 known proteins mutated in X-linked mental retardation, 19 (28%) encode postsynaptic proteins. The high incidence of involvement in cognitive disorders is also found in mouse mutants and indicates that the complexes are functioning as integrated entities or molecular machines and that disruption of different components impairs their overall role in cognitive processes. We also noticed that NRC/MASC genes appear to be more strongly associated with mental retardation and autism spectrum disorders. We propose that systematic studies of PSD and NRC/MASC genes in mice and humans will give a high yield of novel genes important for human disease and new mechanistic insights into higher cognitive functions.

Figure  1.

The PSP of a glutamatergic excitatory synapse. A, The PSP, the complement of postsynaptic proteins that contains ∼1,180 proteins. This set of proteins is organized into complexes of varying sizes (B). The function of postsynaptic complexes is to receive and process signals that mediate neuronal communication and synaptic and behavioral plasticity. NMDA, AMPA, and mGLuR subtypes of glutamate receptors are indicated. B, Venn diagram of constituent protein complexes of the PSP (adapted from Grant9). The total set of PSP (1,180 proteins) is represented as sets of complexes (NRC/MASC, mGLuR5, AMPA, and PSD), and the number of proteins in these sets and overlaps are indicated. Details of the specific proteins are found in table A1.

Figure  2.

Protein-interaction network of the NRC/MASC complex. A network of binary interactions between NRC/MASC proteins was clustered into “modules” with the use of algorithms. These 13 numbered clusters are grouped into three layers: “input,” representing the neurotransmitter receptors and proximal interacting proteins; “processing,” general signaling proteins; and “output,” downstream sets of signaling proteins such as ERK/MAPK pathways. Reprinted with permission from Molecular Systems Biology.

Figure  3.

Modular signaling mechanisms of postsynaptic complexes. The modules of clustered proteins are organized into layers of signaling, with synaptic cleft at the top. Presynaptic information, in the form of a neurotransmitter, enters the postsynaptic signaling machinery via activation of ionotropic and metabotropic transmembrane receptors that are in modules of proximal signaling proteins (blue). From there, signals are passed to a large information-processing module (red) and then are distributed to effector mechanism networks (green), which mediate a functional outcome (dark blue arrow). This signaling machinery provides a high degree of signal integration by protein interaction and orchestration of output responses.

Figure  4.

Human and mouse mutations and the cognitive disorders affecting specific NRC/MASC signaling pathways and other postsynaptic proteins. The NMDA receptor subunits (NR1 and NR2) are linked to MAGUK proteins (SAP102 and PSD-95) that bind SynGAP, which regulates the Ras-ERK-RSK pathway. This pathway regulates transcription (e.g., CREB), cell adhesion (via L1CAM), and AMPA receptors. MAGUKs, including DLG3/SAP102, coordinate the postsynaptic signaling response to NMDA receptor (NR1 and NR2) activation. The MAP kinase pathway is an important limb of this response, leading to changes in transcription factors such as RSK2, which, in turn, send feedback to modify AMPA receptor function and thus produce synaptic plasticity. Note that FMRP, encoded by the FMR1 gene, does not belong to this complex but is involved in the regulation of PSD-95 translation via mGluR activation. Note that the NRC/MASC–associated signaling pathway is involved in MRX as well as MRXS. The molecules are shaded in yellow if there is a known mouse mutation that results in cognitive dysfunction, and red letters indicate if mutation is in a human gene.