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DISC1 Partners Tie Protein to Development, Adult Gene Regulation

26 September 2008. DISC1, or disrupted in schizophrenia, is a promising susceptibility gene candidate for schizophrenia, but exactly how the gene and its protein relate to the pathology of the disease is unclear. Two recent papers from the lab of Akira Sawa at Johns Hopkins University shed some light on the matter. In the September Archives of General Psychiatry, Sawa and colleagues show that by helping to recruit proteins to centrosomes, subcellular structures that are essential for cell morphology and motility, DISC1 may play an important role in neurodevelopment. In the second paper, the researchers focus on another major DISC1 hot spot, the nucleus. Using the venerable fruit fly as a model, the researchers show that in adult animals DISC1 may control gene activation by a master regulatory switch—cyclic AMP. Together the papers support essential roles for DISC1 both during developmental and during adult life.

Centered on the Centrosome
DISC1 was first discovered when a chromosomal rearrangement that disrupts the gene was linked to psychiatric illnesses in an extended Scottish family (see Millar et al., 2000). Since then research into the protein’s role in schizophrenia has intensified (see SRF related news story and SRF news story), but the normal role of the protein has not been completely dissected. In the first paper, Sawa and colleagues address this by examining the role of DISC1 at the centrosome, one of the major subcellular haunts for the protein. Centrosomes are organizing centers for microtubules, long filamentous protein scaffolds that support intracellular transport, cellular structure, and motility.

First author Atsushi Kamiya and colleagues found that DISC1 forms complexes with two other proteins that have been linked to centrosomes, pericentriolar material 1 (PCM1) and Bardet-Biedl syndrome (BBS) proteins. Immunoprecipitating protein from HEK293 cells, the authors found that the central portion of DISC1 binds to BBS proteins, while the N- and C-terminal regions take part in binding to PCM1. Thus DISC1 has distinct binding sites for the two partner proteins. It turns out the same is also true for BBS4, which binds to DISC1 via the second of two tetratricopeptide repeats, while it binds to PCM1 via the third repeat. Likewise, evidence suggests the DISC1 and BBS4 binding sites on PCM1 are also independent, suggesting that all three proteins interact via distinct binding domains.

What would be the function of such a complex? Previous work has shown that DISC1 leads dynein motor proteins to the centrosome (see SRF related news story) and the authors posited that the DISC1/PCM1/BBS4 complex facilitates recruitment of yet other proteins to the same location. To test this idea Kamiya and colleagues suppressed levels of each protein in turn by using RNAi to silence gene translation in PC12 cells. They found that silencing either DISC1 or BBS4 reduced the amount of PCM1 at the centrosome by about the same amount, but that silencing both DISC1 and BBS4 produced a synergistically stronger suppression of PCM1 recruitment. This suggests that both proteins are required for maximal binding of PCM1 to the centrosomes. In support of this idea, knocking down both DISC1 and BBS4 had about the same effect on recruitment of the PCM1 partner ninein to the centrosome as knocking down PCM1 itself.

Kamiya and colleagues used a similar silencing strategy to test how important this tripartite complex is in development. Knocking down any of the three proteins in 15-day-old mouse embryos delayed neuronal migration into growing cortical brain layers and, as with the PC12 cell experiments, knocking down both DISC1 and BBS4 had a much stronger effect than silencing DISC1 alone.

The authors claim that their combined evidence supports a role for the centrosome in the pathology of schizophrenia and possibly other neuropsychiatric disorders, as well as Bardet-Biedl syndrome. (Although the defining features of this rare genetic disorder are retinitis pigmentosa, polydactyly, and obesity, patients with Bardet-Biedl usually present with symptoms that suggest failures of many systems, including neuropsychiatric symptoms.) Genetic variants of PCM1 have been linked to schizophrenia before (see SRF related news story) and in fact the authors provide some additional genetic evidence in this paper, reporting a nonsense mutation in the gene that segregates with schizophrenia in a small family. The authors stress that a mutation in a single family is hardly strong enough data upon which to draw any firm conclusions. “However, the combination of this result with the previous association of PCM1 with SZ and, importantly, the biochemical relationship of PCM1 to DISC1 as it pertains to key neurodevelopmental processes post a compelling argument,” they write.

Whether the DISC1/neurodevelopmental theory of schizophrenia will hold water remains to be seen. But even if it does not, that does not eliminate a role for DISC1 in the disease. The protein still has a role to play in adult animals, as Sawa and colleagues demonstrated in the second paper.

Narcoleptic in the Nucleus
In the September Molecular Psychiatry, first author N. Sawamura and colleagues report that they have developed a transgenic model for DISC1 activity by expressing human DISC1 in the fruit fly. Flies do not possess a DISC1 equivalent in their genome, but they do have many fly orthologs of human DISC1 binding partners. Like fly models featuring α-synuclein, a Parkinson disease-linked protein that is absent from fruit flies, this model should allow researchers to probe the interactions and function of DISC1 in living animals.

Sawamura and colleagues introduced the human gene for DISC1 into the fly under the control of an inducible promoter. This allowed them to grow the flies to adulthood while the DISC1 gene was quiescent. When they turned on the gene in adult male flies, they found it put the animals asleep. Why it had this effect is not clear, but the DISC1 protein turned up mainly in the nucleus, suggesting that it may influence gene activation. To address this, the researchers probed the relationship between DISC1 and another of its known binding partners, the transcription factor ATF4/CREB2, which has been linked to regulation of brain function, including long-term memory.

Using a reporter system to measure activity of ATF4/CREB2, the researchers found that DISC1 suppressed the transcription factor and that the two directly interact, through the “LZ” domain on DISC1. The researchers found that DISC1 also binds to the transcriptional co-repressor N-CoR, but through a different region on the protein, suggesting that DISC1 can bind both ATF4/CREB2 and N-CoR at the same time. “These results suggest that, by recruiting N-CoR to an ATF4/CREB2-containing complex as a common scaffold, DISC1 might modulate gene transcription regulated by ATF4/CREB2," the authors write, and that is just what they found. ATF4/CREB2 can suppress genes activated by cAMP response elements, but adding DISC1 suppressed that activity even further.

Together, the two papers show that the actions of DISC1 are varied and complex. Which actions are directly linked to schizophrenia, if any, remains to be determined, as do the ramifications of DISC1 genetic variation. It is interesting, for example, that the fly model exhibits sleep disturbances, which are reported in almost all psychiatric conditions. “It is also intriguing to examine genetic variations that can potentially affect interaction of DISC1 with ATF4/CREB2 or N-CoR, such as non-synonymous polymorphism Leu600Phe, in association with sleep characteristics in human subjects, including patients with various psychiatric diseases,” write the authors.—Tom Fagan.

Kamiya A, Tan PL, Kubo K-I, Engelhard C, Ishizuka K, Kubo A, Tsukita S, Pulver AE, Nakajima K, Cascella NG, Katsanis N, Sawa A. Recruitment of PCM1 to the centrosome by the cooperative action of DISC1 and BBS4. Arch. Gen. Psych. September 2008;65:996-1006. Abstract

Sawamura N, Ando T, Maruyama Y, Fujimoro M, Mochizuki H, Honjo K, Shimoda M, Toda H, Sawamura-Yamamoto T, Makuch LA, Hayashi A, Ishizuka K, Cascella NG, Kamiya A, Ishida N, Tomoda T, Hai T, Furukubo-Tokunaga K, Sawa A. Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly. Mol. Psych. September 2008. Abstract

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