Schizophrenia has yet to find its breakthrough treatment despite its global prevalence. The DISC1 protein’s interactome role in neurodevelopment makes it a desirable target. Issues arise with the lack of structural data. DISC1 has been elusive until 2017 when the C-terminal domain complexed with Ndel1 was resolved with NMR. Psychotic disorders affect communities worldwide with the most common disorder being schizophrenia (Holder & Wayhs, 2014), which is interesting to scientists and clinicians since there are currently no universally efficacious treatments (Willsey, et al., 2018). Part of what makes schizophrenia so difficult to treat comes from the complicated network of contributing factors that lead to onset including genetic, biochemical, and environmental influences on the person (Nascimento & Martins-de-Souza, 2015). A person may also display many symptoms classified as positive or negative that require different treatments; positive symptoms include those which add to a person’s behaviors like delusions, hallucinations, disorganized speech while negative includes those which remove a person’s behaviors like catatonia and loss of emotional expression or motivation (Holder & Wayhs, 2014).
The symptoms are further complicated by the expense of treatments and by the tendency for a person to experience adverse effects from available treatments (Holder & Wayhs, 2014). Proteomic (Nascimento & Martins-de-Souza, 2015) and genetic studies (Devine, et al., 2016) have identified a slew of molecular targets with promising connection to the illness. One of these targets includes Disrupted-in-Schizophrenia 1, DISC1, a protein with incomplete characterization both functionally (Devine, et al., 2016) and structurally (Yerabham, et al., 2017). Mutations in the disc1 gene are linked to schizophrenia although it is important to consider that genome wide association studies do not confirm sole responsibility of Disc1 for the disorder (Devine, et al., 2016). Rather, it is the intracellular connectivity of the protein and the role of DISC1 in neurogenesis that makes the protein an attractive target for therapeutics (Ye, et al., 2017).
The protein, DISC1, was identified when a Scottish family diagnosed with schizophrenia among other mental illnesses had their genome examined and found a translocation in disc1 where the gene located on chromosome 1 was found on chromosome 11, t(1:11) (Yerabham, et al., 2017). Attempts to define the structure of DISC1 have been limited due to its lack of homology to other known proteins and poorly conserved functional sequences (Millar, et al., 2005). A study by Millar, et al. (2005) predicted two major domains including an N-terminal head with conserved nuclear localization signals despite being poorly conserved otherwise and a C-terminus with a helical tail. Over 10 years later bioinformatics still only provided an estimation of structural disorder in the first 325 amino acids while the remaining 326-854 amino acids were helical or coiled (Yerabham, et al., 2017). Expression of Soluble Protein by Random Incremental Truncation (ESPRIT) of recombinant DISC1 in E. coli has led to the observation that DISC1 bears four consistently stable regions, D, I, S, and C from the N-terminal to the C-terminal ends of the protein, respectively (Yerabham, et al., 2017).
Table 1 demonstrates the location of each region (Yerabham, et al., 2017). The D region is high in ?±-helical content determined by circular dichroism (CD) and is the only region in the N-terminal; the I region displays structural qualities and CD also shows helical shape; the S region exhibits an elongated and helical form suggested by analytical ultracentrifugation (AUC) sedimentation velocity (SV) and CD, respectively; the C region also used AUC SV and CD to demonstrate an elongated and somewhat disordered helical shape (Yerabham, et al., 2017). Further, a study by Ye, et al. (2017) imaged the C-terminal tail when bound to Ndel1, a protein involved in mitosis and essential for proper neurodevelopment, with solution NMR to determine two ?± -helical structures with atomic resolution. The DISC1-Ndel1 complex revealed a conserved antiparallel hairpin figure in DISC1 (Figure C) and when Ndel1 is bound it adds a third ?±-helix to the 2-helix hairpin (Figure A) which produces a hydrophobic core (Figure G) (Ye, et al., 2017). DISC1 has the potential to assume many functional roles as there are hundreds of binding partners described (Ye, et al., 2017). The N-terminus was the focus of Millar, et al.’s studies (2005) which used GFP- and V5-peptide tags for immunoprecipitation and immunofluorescent imaging to support mitochondrial targeting by the N-terminal domain of DISC1. Ye, et al.’s (2017) investigation suggests the complex regulates Ndel1’s kinetochore localization in HeLa cells by properly binding DISC1 to Ndel1 leading to timely mitosis.
Radial glial cells (RGCs), relevant to the ventricular zone in neural stem cells of the embryonic cortex, were also tested in vivo using mouse models to test DISC1-Ndel1 function and revealed a regulating role for RGC cell-cycle progression as well (Ye, et al., 2017). Ye, et al. (2017) continued to examine DISC1-Ndel1 for roles in neurogenesis by testing human induced pluripotent stem cells (iPSCs) which were differentiated into forebrain-specific organoids and found reduced proliferation of neural stem cells when DISC1-Ndel1 binding was inhibited. Further, it was observed in forebrain-specific organoids containing the naturally occurring disc1 mutation that cell-cycle progression of RGCs throughout mitosis was delayed, confirming previous testing about DISC1-Ndel1 functions (Ye, et al., 2017). DISC1 has also been implicated in regulating dendritic N-methyl-D-aspartate receptor (NMDAR) dynamics which are necessary for synaptic plasticity and cognitive processes (Malavasi, et al., 2018).
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