Role of DISC1 in Neuronal Trafficking and its Implication in Neuropsychiatric Manifestation and Neurotherapeutics

Abstract

Disrupted-in-schizophrenia 1 (DISC1) was initially identified as a gene disrupted by a translocation mutation co-segregating with a variety of psychotic and mood disorders in a Scottish pedigree. In agreement with this original finding, mouse models that perturb Disc1 display deficits of behaviors in specific dimensions, such as cognition and emotion, but not a motor dimension. Although DISC1 is not a risk gene for sporadic cases of specific psychiatric disorders defined by categorical diagnostic criteria (e.g., schizophrenia and major depressive disorder), DISC1 is now regarded as an important molecular lead to decipher molecular pathology for specific dimensions relevant to major mental illnesses. Emerging evidence points to the role of DISC1 in the regulation of intracellular trafficking of a wide range of neuronal cargoes. We will review recent progress in this aspect of DISC1 biology and discuss how we could utilize this body of knowledge to better understand the pathophysiology of mental illnesses.

Knock-Down of Hippocampal DISC1 in Immune-Challenged Mice Impairs the Prefrontal–Hippocampal Coupling and the Cognitive Performance Throughout Development

“…2013 ), a wealth of data documented its relevance for psychiatric conditions ( Tomoda et al. 2016 , 2017 ; Trossbach et al. 2016 ; Kakuda et al.…”

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity

“…A recent study proposed DISC1 as a player in neurodevelopment and synaptic function (Niwa et al, 2016), and DISC1 knockdown (focused on DISC1 loss-of-function) directly affected the expression of relevant proteins involved in these processes (Kamiya et al, 2006). In addition, DISC1 plays roles in various processes of neurogenesis and synapses maintenance (Brandon and Sawa, 2011), and in the regulation of intracellular trafficking of a wide variety of neuronal cargoes (Tomoda et al, 2017). The most recognized mechanistic molecular hypothesis proposes DISC1 role as a scaffold hub protein interacting with proteins involved in the dopamine pathway, including the dopamine D2 receptor and vesicular monoamine transporter (Trossbach et al, 2016; Zheng et al, 2018), but also interacting with a large number of synaptic and cytoskeletal proteins (Tropea et al, 2018).…”

Characterization of striatal phenotypes in heterozygous Disc1 mutant mice, a model of haploinsufficiency

“…DISC1 and its binding partners have been shown to regulate a number of cellular functions, such as neuronal migration, axon extension, dendritic differentiation, mitochondria motility, cargo transport, and synaptic plasticity. Thus, a variety of psychiatric phenotypes may be derived if this gene is disrupted (Bradshaw & Porteous, 2012;Brandon & Sawa, 2011;Lipina & Roder, 2014;Shao et al, 2017;Tomoda, Hikida, & Sakurai, 2017;Tropea, Hardingham, Millar, & Fox, 2018).…”