A couple of recently published papers have provided insights into the cell physiology of DISC1. Although DISC1 is one of the most extensively studied susceptibility genes for psychiatric illness, the promoter of DISC1 has not been characterized so far. In a systematic approach based on luciferase reporter genes, Walker et al. (Walker et al., 2012) describe a repressive and an enhancing promoter region upstream of the transcription start. The DISC1 promoter is negatively regulated by FOXP2; hence, affected FOXP2 mutation carriers might show a higher DISC1 expression. Therefore, it would be interesting to know if these FOXP2 mutation carriers also display a higher level of insoluble DISC1, since increased expression leads to an increase of insoluble DISC1 (Leliveld et al., 2008). As a result, and possibly through aggregation, DISC1 loses its ability to bind to specific interaction partners, thereby disrupting some cellular pathways (Atkin et al., 2012) and potentially leading to other gain-of-function effects. In this context, Malavasi et al. (Malavasi et al., 2012) report in detail on the control of DISC1 over the transcriptional activity of ATF4. ATF4 itself acts as a key protein in emotional learning and memory via its ability to repress CREB activity. The authors provide intriguing results on how full-length DISC1 protein and its non-synonymous polymorphisms 37W and 607F differentially inhibit ATF4 activity by distinct mechanisms. Both genetic variants—the rare, putatively causal substitution 37W and the common variant 607F—exclude the protein from the nucleus, thereby reducing ATF4 inhibition.

Eykelenboom et al. (Eykelenboom et al., 2012) also report on an abnormal subcellular distribution of mutated DISC1 by elegantly expanding the concept of DISC1 translocation-derived fusion proteins proposed previously (Zhou et al., 2008; Zhou et al., 2010). This is the first paper to confirm the existence of three different transcripts from the translocated DISC1 gene, potentially giving rise to DISC1 proteins adding 1, 60 or 69 amino acids to the N-terminus (1-597). Upon biophysical characterization, the two larger proteins termed CP60 and CP69 exhibit a higher helical amount and larger protein assemblies. When the recombinant fusion proteins were expressed in cells, they mediated abnormal mitochondrial localization and altered mitochondrial membrane potential.

The last two publications show that altered DISC1 protein structure, ranging from single amino acid changes to large, chimeric fusion proteins, can culminate in changes of the protein cellular distribution, oligomerization status, and abnormal cellular function. Increasing evidence suggests that defined DISC1 protein species have particular local functions within the neuron or glia cells, and that at least a part of the DISC1-mediated pathology is dependent on abnormal cellular distribution of the protein.

References:

Atkin TA, Brandon NJ, Kittler JT. Disrupted in Schizophrenia 1 forms pathological aggresomes that disrupt its function in intracellular transport. Hum Mol Genet . 2012 May 1 ; 21(9):2017-28. Abstract

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 May 16. Abstract

Leliveld SR, Bader V, Hendriks P, Prikulis I, Sajnani G, Requena JR, Korth C. Insolubility of disrupted-in-schizophrenia 1 disrupts oligomer-dependent interactions with nuclear distribution element 1 and is associated with sporadic mental disease. J Neurosci . 2008 Apr 9 ; 28(15):3839-45. 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 Jun 15 ; 21(12):2779-92. 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

Zhou X, Geyer MA, Kelsoe JR. Does disrupted-in-schizophrenia (DISC1) generate fusion transcripts? Mol Psychiatry . 2008 Apr ; 13(4):361-3. Abstract

Zhou X, Chen Q, Schaukowitch K, Kelsoe JR, Geyer MA. Insoluble DISC1-Boymaw fusion proteins generated by DISC1 translocation. Mol Psychiatry . 2010 Jul 1 ; 15(7):669-72. Abstract

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