Psychiatric Disorders: Multiple Pathways to DISC1-Related Disease?

RESEARCH HIGHLIGHTS

unlike wild-type and S704C DISC1, In contrast to the phenotypes PSYCHIATRIC DISORDERS were unable to stimulate WNT- observed with FEZ1 knockdown, induced transcription and prolifera‑ knockdown of NDEL1 expression Multiple pathways to tion (a process regulated by WNT caused the formation of ectopic den‑ signalling) in murine neuroblastoma drites in adult-born dentate granule DISC1‑related disease? cells, and that the absence of such cells and the abnormal positioning of effects was due to a reduction in the these cells in granule cell layers. Such variant’s GSK3β‑binding capacity. phenotypes are also observed follow‑ They also showed that expression ing knockdown of DISC1 expression, of S704C DISC1 but not the other suggesting that FEZ1 and NDEL1 reg‑ variants rescued neural progenitor ulate adult-born neuron development proliferation defects in embryonic through parallel pathways involving mouse brain following knockdown DISC1. Supporting this assertion, the of DISC1 and that transcription simultaneous knockdown of NDEL1 assays involving human-derived and FEZ1 did not elicit any synergistic lymphoblast cell-lines yielded effects on newly born neurons, and a results that were in line with the series of immunoprecipitation experi‑ previous data. ments showed that NDEL1 and FEZ1 Thus, the R264Q, L607F and A83V did not directly interact; rather, they DISC1 variants may increase the risk both bound DISC1. of psychiatric disease through impair‑ Alongside their studies in mice, ment of canonical WNT signalling Ming and colleagues undertook a and neurodevelopment. Interestingly, genetic association study of FEZ1 S704C DISC1 may impair neu‑ with schizophrenia, from which they rodevelopment through a different uncovered an epistatic interaction pathway, as the authors found that this between a FEZ1 polymorphism and variant — unlike R264Q, L607F and the allele encoding S704C DISC1. A83V DISC1 — was unable to rescue This finding is consistent with the WNT-independent neuronal migra‑ synergistic effect of knocking down The scaffolding protein disrupted in tion deficits in mouse embryonic the expression of FEZ1 and DISC1 in schizophrenia 1 (DISC1) has multiple cortex following knockdown of DISC1 newly born neurons and shows how roles in neurodevelopment. Both expression. polymorphisms in DISC1 and associ‑ rare and common variants of this In the second study, Ming ated genes may combine to increase protein may influence psychiatric and colleagues examined the role the risk of disease. phenotypes, although it remains of DISC1 in the development of Taken together, these studies unclear how DISC1 is mechanisti‑ adult-born neurons, focusing their suggest pathways whereby DISC1 cally linked to disease. Now, two attention on the previously reported variants impair neurodevelopment studies provide evidence for possible interactions of DISC1 with two and increase susceptibility to schizo‑ DISC1‑mediated pathophysiological proteins implicated in neural devel‑ phrenia. Moreover, they highlight pathways. opmental processes: nuclear distri‑ how mechanistic insights into psychi‑ Tsai and colleagues examined bution protein nudE-like 1 (NDEL1) atric disease may be garnered from the functional significance of three and fasciculation and elongation complex genetic findings. these studies common DISC1 variants (R264Q, protein‑ζ1 (FEZ1). They found that Darran Yates suggest pathways L607F and S704C DISC1) and one knockdown of FEZ1 expression whereby DISC1 rare variant (A83V DISC1), which in the dentate gyrus accelerated ORIGINAL RESEARCH PAPERS Singh, K. K. et al. variants impair they identified from a group of dendritic growth and caused an Common DISC1 polymorphisms disrupt Wnt/ healthy individuals and patients with increase in soma size in newly born GSK3β signaling and brain development. Neuron neurodevelopment 72, 545–558 (2011) | Kang, E. et al. Interaction psychiatric disorders. neurons. Moreover, simultaneous and increase between FEZ1 and DISC1 in regulation of DISC1 can bind glycogen syn‑ knockdown of DISC1 and FEZ1 neuronal development and risk for schizophrenia. susceptibility to Neuron 72, 559–571 (2011) thase kinase 3β (GSK3β), activating further accelerated dendritic growth, FURTHER READING Brandon, N. J. & Sawa, A. schizophrenia canonical WNT signalling. Using in suggesting that in adult-born neu‑ Linking neurodevelopmental and synaptic vitro assays, the authors showed that rons, both proteins regulate dendrite theories of mental illness through DISC1. Nature Rev. Neurosci. 12, 707–722 (2011) A83V, R264Q and L607F DISC1, development.