Linking neurodevelopmental and synaptic theories of mental illness through DISC1

Abstract

Recent advances in our understanding of the underlying genetic architecture of psychiatric disorders has blown away the diagnostic boundaries that are defined by currently used diagnostic manuals. The disrupted in schizophrenia 1 (DISC1) gene was originally discovered at the breakpoint of an inherited chromosomal translocation, which segregates with major mental illnesses. In addition, many biological studies have indicated a role for DISC1 in early neurodevelopment and synaptic regulation. Given that DISC1 is thought to drive a range of endophenotypes that underlie major mental conditions, elucidating the biology of DISC1 may enable the construction of new diagnostic categories for mental illnesses with a more meaningful biological foundation.

Figure 1. The ‘DISC1 interactome’ points towards the multiple functions of DISC1 during neuronal development

The important DISC1 interactions relevant for this review are highlighted in this figure. They are a small subset of the original dataset, which have all been confirmed in other biological systems^,,,,,,,,. The functional relevance of the different interactions is highlighted on the perimeter of the cartoon, with arrows representing the chronological order of events during development. DISC1, Disrupted-in-schizophrenia-1; GSK3β, Glycogen synthase kinase 3β; Dixdc1, DIX domain containing 1; NDEL1, Nuclear distribution protein nudE-like 1; LIS1, Lissencephaly protein 1; PCM1, Pericentriolar material 1; BBS, Bardet-Biedl Syndrome protein; PDE4; Phosphodiesterase type 4; Kal-7, Kalirin-7; TNIK, TRAF2 and NCK-interacting protein kinase; and PSD95; Postsynaptic density protein 95.

Figure 2. DISC1 protein interaction domains and relationship to the location of rare human variants associated with mental disorders

Diagram of protein-protein interaction domains mapped onto DISC1 and key DISC1 genetic variants (top) possibly associated with mental disorders^{–,,,,,,,,,,}. PCM1, Pericentriolar material 1; BBS, Bardet-Biedl Syndrome; Dixdc1, DIX domain containing 1; GSK3β Glycogen synthase kinase 3β; LIS1, Lissencephaly protein 1; NDE1, Nuclear Distribution protein NudE homolog 1; NDEL1, Nuclear Distribution Protein NudE-Like 1; PDE4, Phosphodiesterase type 4; TNIK, TRAF2 and NCK-interacting protein kinase; and Kal-7, Kalirin-7. Genetic variants at Q264R, L607F, and S704C (common variants) are associated with schizophrenia (SZ). Furthermore, associations with L607F (*) and S704C (#) are reported for schizoaffective (SA) and major depression (MD), respectively. BP, bipolar disorder. Please note that the binding sites have been mapped using a range of different approaches so the resolution achieved in individual interactions is different (dotted lines are sites awaiting fine mapping).

Figure 3. DISC1 function during early development

DISC1 regulates both progenitor cell proliferation and postmitotic neuronal migration. In proliferating progenitors, DISC1 inhibits premature cell cycle exit and differentiation of proliferating progenitors: In these cells, DISC1 inhibits GSK3β through direct physical interaction, which in turn reduces β-catenin phosphorylation and stabilizes β-catenin. Green circles with the black and white stripe indicate the rapid degradation of this protein. In postmitotic neurons DISC1 preferentially interacts with proteins in the dynein motor complexes associated with microtubules (pink tubes) and the centrosome (two grey connected ovals), including BBS proteins, which mediates neuronal migration^,. As corticogenesis progresses, the affinity of DISC1 for GSK3β is reduced, likely through phosphorylation at S713; in contrast, the interaction with BBS proteins is increased. Furthermore, DISC1 regulates the transition from neuronal progenitor proliferation to neuronal migration through an increase in phosphorylation of DISC1 at S710, which occurs at embryonic stage E13-15: DISC1/BBS binding recruits DISC1 away from a GSK3β-regulated Wnt/β-catenin activity and thus contributes to the switch from neuronal progenitor proliferation to neuronal migration. DISC1, Disrupted-in-Schizophrenia-1; BBS, Bardet-Biedl Syndrome protein; and GSK3β, Glycogen synthase kinase 3β.

Figure 4. DISC1 function at the synapse

DISC1 has been recently shown to regulate dendritic spines through regulation of a Kal-7-Rac1-PAK pathway and synapse maintenance through regulation of TNIK. DISC1 enhances binding of Kal-7 and PSD95, blocking the access of Kal-7 to Rac1. Once the NMDA receptor is activated, these protein interactions are weakened, allowing the free access of Kal-7 to Rac1, leading to the activation of Rac1. Regulation of Kal-7’s access to Rac1 by DISC1 in an activity-dependent fashion is crucial for the proper maintenance of the synaptic spine. It is currently unknown if TNIK is found in similar or different synapses as DISC1 and kalirin-7 complexes. Inhibition of TNIK function leads to the selective degradation of a number of key postsynaptic proteins including GluR1 and the scaffold protein PSD-95 and a loss of GluR1 from the membrane surface. The degradation of protein is either lysosomal or proteasomal mediated. The E3 ubiquitin ligase, Neuronal precursor cell-expressed developmentally downregulated protein 4-1 (Nedd4-1)^,, has been identified as a TNIK binding partner. Nedd4-1 has been shown to ubiquitinate GluR1 and drive its lysosomal degradation. Hypothetically, inhibition of TNIK, could lead to an elevated activity of Nedd4-1, increased ubiquitination of GluR1 (or other proteins) and lead to their subsequent degradation. An integrated view of these two pathways is currently unavailable, though both pathways have common end-points related to actin cytoskeleton regulation and AMPA receptor trafficking. Independent studies suggest that TNIK may regulate GluR1 endocytosis through a complex with the E3 ligase Nedd4-1. Complexes of DISC1 with PDE4, GSK3 and NDEL1 (not shown) are also found at the synapse but their function is not known. DISC1, Disrupted-in-Schizophrenia-1; TNIK, TRAF2 and NCK-interacting protein kinase; Nedd4-1, E3 ubiquitin ligase, Neuronal precursor cell-expressed developmentally downregulated protein 4-1; GSK3β, Glycogen synthase kinase 3β; NDEL1, Nuclear distribution protein nudE-like 1; LIS1, Lissencephaly protein 1; PDE4; Phosphodiesterase type 4; Kal-7, Kalirin-7; and PSD95; Postsynaptic density protein 95; NMDAR, N-methyl-D-aspartic acid type glutamate receptor; AMPAR, α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionatetyoe glutamate receptor.