18 May 2012. The many functions of the famous psychiatric disorder risk gene, disrupted in schizophrenia 1 (DISC1), continue to be revealed. In a trio of studies from the University of Edinburgh in the United Kingdom, all published in Human Molecular Genetics, researchers explore the promoter region DISC1 and shed light on new mechanisms that may underlie DISC1-mediated dysfunction in psychiatric illnesses, including roles in mitochondria and the nucleus.
The scaffolding protein DISC1 first entered the schizophrenia arena when a chromosomal translocation that disrupts the gene was discovered in a Scottish family fraught with mental illness. The function of DISC1 in both health and disease has since been enthusiastically studied, with new papers appearing regularly (see SRF related news story). At this point, one thing is very clear—DISC1 plays a variety of roles in a number of important brain processes, including neurogenesis (see SRF related news story), neuronal development, signaling, spine regulation, and synaptic function (Brandon and Sawa, 2011). These three studies add to this growing pile of evidence that DISC1 is a critical cellular component.
In one study, published online April 30, J. Kirsty Millar and colleagues used lymphoblastoid cell lines from translocation carriers, who exhibit 50 percent lower expression of DISC1 (see SRF related news story), to show that the translocation results in the production of abnormal transcripts and proteins, causing severe mitochondrial dysfunction. The problem arises when DISC1 fuses with the chromosome 11 gene DISC1 fusion partner 1 (DISC1FP1), resulting in chimeric proteins consisting of exons 1-8 of the DISC1 sequence, plus one, 60, or 69 amino acids (termed CP1, CP60, and CP69, respectively).
First author Jennifer Eykelenboom and colleagues found that the additional 69 amino acids in CP69 modify the protein’s secondary structure, resulting in a higher α-helical content and the formation of large, stable protein assemblies. The authors speculate that these might be responsible for the DISC1 aggregates that have been observed in postmortem tissue from patients with mental illness (Corth et al., 2009), and predict a similar situation for CP60. In addition, in both cell lines and primary neuronal cultures, CP60 and CP69 were mainly targeted to mitochondria, and their expression altered mitochondrial morphology by inducing clustering and leading to a loss of mitochondrial membrane potential. Thus, these chimeric proteins induce severe mitochondrial dysfunction. Future studies are needed to confirm the effects of CP60 and CP69 in brain tissue from translocation carriers.
Trouble targeting the nucleus
In a second study led by Millar, published online March 28, first author Elise Malavasi and colleagues detailed a role for schizophrenia risk variants in DISC1 in its distribution in another cellular compartment—the nucleus. They found that a rare variant termed 37W, as well as a more common one known as 607F, both prevent targeting of DISC1 to the nucleus in a dominant-negative fashion. In addition, the researchers demonstrated that DISC1 inhibits the activity of transcription factor ATF4, known to be upregulated in response to cellular stress, suggestive of a role for DISC1 in transcriptional regulation. This effect of DISC1 was attenuated in carriers of 37W and 607F. In fact, DISC1 overexpression decreased CRE-dependent transcription in response to endoplasmic reticulum stress, and this effect was again diminished in the risk variant carriers.
“DISC1 functions as a hub protein whose principal role is to modulate various cellular processes…," Malavasi and colleagues write. "Sequence changes in DISC1 that disrupt its normal compartmentalization and protein interactions are therefore likely to have functional consequences, and may highlight biological processes involved in psychopathology.”
Probing the promoter
In a third study, published online April 4 and led by Rosie Walker, researchers characterized the promoter region of DISC1, finding that it lacked many of the common components of other promoter regions, such as a TATA box, initiator, and downstream promoter element. The researchers did identify a region upstream from the transcription start site that increases promoter activity, as well as one further upstream that decreases it. Walker and colleagues also found that DISC1 promoter activity, and protein levels, are inhibited by the transcription factor FOXP2. Of note, mutations in FOXP2 lead to a genetic form of developmental verbal dyspraxia, a disorder of speech and language (Lai et al., 2001). The authors reported that two of these mutations reduce the inhibitory effect of FOXP2 on DISC1 promoter activity, providing “a point of molecular convergence between neurodevelopmental disorders that have traditionally been viewed as diagnostically distinct.”—Allison A. Curley.
Eykelenboom JE, Briggs GJ, Bradshaw NJ, Soares DC, Ogawa F, Christie S, Malavasi EL, Makedonopoulou P, Mackie S, Malloy MP, Wear MA, Blackburn EA, Bramham J, McIntosh AM, Blackwood DH, Muir WJ, Porteous DJ, Millar JK. A t(1;11) translocation linked to schizophrenia and affective disorders gives rise to aberrant chimeric DISC1 transcripts that encode structurally altered, deleterious mitochondrial proteins. Hum Mol Genet . 2012 Apr 30. Abstract
Walker RM, Hill AE, Newman AC, Hamilton G, Torrance HS, Anderson SM, Ogawa F, Derizioti P, Nicod J, Vernes SC, Fisher SE, Thomson PA, Porteous DJ, Evans KL. The DISC1 promoter: characterization and regulation by FOXP2. Hum Mol Genet . 2012 Apr 4. Abstract
Malavasi EL, Ogawa F, Porteous DJ, Millar JK. DISC1 variants 37W and 607F disrupt its nuclear targeting and regulatory role in ATF4-mediated transcription. Hum Mol Genet . 2012 Mar 28. Abstract