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