DISC1: Structure, Function, and Therapeutic Potential for Major Mental Illness

<i>Disrupted in schizophrenia 1 (DISC1)</i> is well established as a genetic risk factor across a spectrum of psychiatric disorders, a role supported by a growing body of biological studies, making the DISC1 protein interaction network an attractive therapeutic target. By contrast, there is a relative deficit of structural information to relate to the myriad biological functions of DISC1. Here, we critically appraise the available bioinformatics and biochemical analyses on DISC1 and key interacting proteins, and integrate this with the genetic and biological data. We review, analyze, and make predictions regarding the secondary structure and propensity for disordered regions within DISC1, its protein-interaction domains, subcellular localization motifs, and the structural and functional implications of common and ultrarare <i>DISC1</i> variants associated with major mental illness. We discuss signaling pathways of high pharmacological potential wherein DISC1 participates, including those involving phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3). These predictions and priority areas can inform future research in the translational and potentially guide the therapeutic processes

Evaluated immunoassay kits, including assay characteristics and CSF dilutions.

<p>Evaluated immunoassay kits, including assay characteristics and CSF dilutions.</p

Short-term biotemporal stability of measurable and technically precise analytes in CSF.

<p>Biotemporal variation between paired samples over an 8-week interval for (a) core AD biomarkers, (b) Aβ and tau-independent markers of neurodegeneration, (c) metabolic and oxidative stress markers, (d) markers of inflammation and inflammatory modulators, and (e) vascular injury markers. Samples plotted for each analyte, with baseline concentrations connected to corresponding paired week 8 concentrations. Plotted using a log scale, all units converted to pg/mL. <i>N</i> = 9 pairs for each analyte, concentrations averaged across three technical replicates. Each analyte plot is labeled with the median biotemporal CV (%). A CV < 15% indicated low intra-individual variation.</p

Baseline demographic and clinical characteristics of study participants.

<p>Baseline demographic and clinical characteristics of study participants.</p

Structure of the assay stability evaluation scheme.

<p>Duplicate samples were located on individual plates as shown, to allow for assessment of intra- and inter-assay precision and biotemporal stability of analyte measures. T1 and T2 denote repeat-collected CSFs from the same individual; A-C indicate different aliquots of the same CSF sample. <i>N</i> = 35 samples were included on each individual plate, in addition to a standard curve and spiked controls.</p

Intra-individual biostability of analyte measurements between repeat-collected CSFs.

<p>Intra-individual biostability of analyte measurements between repeat-collected CSFs.</p