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Linking neurodevelopmental and synaptic theories of mental illness through DISC1

Key Points

  • Disrupted in schizophrenia 1 (DISC1) was identified in a Scottish family through characterization of a balanced chromosomal translocation that was found to associate with major mental illnesses (schizophrenia, bipolar disorder and depression). Additional studies have shown that DISC1 is associated with endophenotypes underlying these disorders.

  • Identification of the 'DISC1 interactome' has enabled discovery of roles for DISC1 in brain development and function. This has been complemented with extensive RNA interference (RNAi) experimental approaches and the use of DISC1 animal models.

  • DISC1 has been shown to have a key role in neurodevelopmental processes, in particular in regulating cortical development (progenitor proliferation and neuronal migration) and hippocampal neurogenesis.

  • DISC1 has been found to have a key role in synapse function. In particular, interactions with the proteins kalirin 7 and TRAF2- and NCK-interacting kinase (TNIK) have suggested roles in synapse formation and maintenance.

  • DISC1 is considered an important tool for drug discovery approaches. Interactions between DISC1 and proteins, such as phosphodiesterase 4 (PDE4) and glycogen synthase kinase 3 (GSK3), previously suggested as therapeutic targets for mental illnesses, have implicated DISC1 as a possible interacting hub for drug targets. DISC1 animal models are also being considered for drug discovery screening.

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.

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Figure 1: The DISC1 interactome points towards the multiple functions of DISC1 during neuronal development.
Figure 2: DISC1 protein interaction domains and relationship to the location of rare human variants associated with mental disorders.
Figure 3: DISC1 function during early development.
Figure 4: DISC1 function at the synapse.

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Acknowledgements

We thank Y. L. Lema for preparing figures and organizing the manuscript and D. Blackwood for preparation of box 1. We also thank H. Jaaro-Peled, K. Ishizuka and M. Niwa for critical reading of the manuscript. Grant supports (A.S.): from MH-084018, MH-94268 Silvo O. Conte centre, MH-069853, MH-085226, MH-088753, MH-092443, Stanley, RUSK, S-R foundations, NARSAD and Maryland Stem Cell Research Fund.

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Nicholas J. Brandon is a full-time employee of Pfizer, Inc. Akira Sawa declares no competing financial interests.

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Glossary

Domains

These are a specific cluster of symptoms that can be grouped together and described by a single descriptive neuropsychological or clinical construct: for example, information processing, working memory and attention.

Balanced chromosomal translocation

Refers to an exchange of genetic material between non-homologous chromosomes with no overall loss or gain of genes.

Breakpoint

Refers to the site of fusion of two chromosomes after a chromosomal rearrangement such as a balanced translocation.

Endophenotypes

These are also referred to as 'intermediate phenotypes'. In schizophrenia, they do not refer to the symptoms but to the underlying phenotypes that are likely to contribute to symptoms. These include working memory deficits and electrophysiological measures such as P300 deficits. To be classified as an endophenotype, the measure must be inherited, associated with the disease and be 'state-independent'.

Nonsynonymous mutation

A mutation in a gene that leads to a change in an amino acid sequence.

Induced pluripotent stem cells

(iPS cells). These are created from differentiated cell types — for example, fibroblasts — that are reprogrammed by a cocktail of transcription factors (or other approaches) back to a pluripotent state. These cells can now be differentiated into cells of distinct lineages: for example, neurons.

Induced neural cells

(iN cells). These are created from differentiated cell types — for example, fibroblasts — that are reprogrammed directly to a neuronal lineage by a cocktail of transcription factors.

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Brandon, N., Sawa, A. Linking neurodevelopmental and synaptic theories of mental illness through DISC1. Nat Rev Neurosci 12, 707–722 (2011). https://doi.org/10.1038/nrn3120

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