Novel findings on the role of DISC1 and mitochondrial function
One of the most interesting genetic leads for schizophrenia and affective disorders is a balanced translocation on chromosome 1, leading to the disruption of DISC1 (disrupted-in-schizophrenia 1). The translocation is observed in a Scottish family with a history of major psychiatric disorders, and the linkage with psychiatric disorders has been thoroughly studied and confirmed (Blackwood et al., 2001). While the function of DISC1 is not entirely known, it has a strong connection with mitochondria. Animal models and studies in cell lines and cortical cultures showed that the protein localizes predominantly to mitochondria (Brandon et al., 2005; James et al., 2004; Morris et al., 2003). Expression of truncated DISC1 in cell lines, mimicking the translocation breakpoint in the Scottish pedigree, led to decreased mitochondrial localization (Brandon et al., 2005; Millar et al., 2005). Furthermore, overexpression of truncated DISC1 isoforms induced abnormal mitochondrial morphologies, and affected mitochondrial fission and fusion (Millar et al., 2005).

Mitochondrial pathology has been implicated in schizophrenia as well as affective disorders, and has been verified in a variety of experimental paradigms (for a recent review, see Clay et al., 2010). A recent article by Park et al. (Park et al., 2010) further elaborates on the link between mitochondrial function and DISC1. The authors examined the interaction of DISC1 with mitofilin, a transmembrane protein of the inner mitochondrial membrane with critical functions in mitochondrial morphology, mitochondrial fission, and fusion. In previous publications, mitofilin has been shown to interact with DISC1 (see, e.g., Camargo et al., 2007), but Park et al. took it one step further. In their study, the authors demonstrate that DISC1 affects protein levels of mitofilin by increasing ubiquitination and proteasome-mediated degradation. Reduction or truncation of DISC1 affected the activity of the electron transport chain and led to a decrease in ATP levels. Moreover, reduction in DISC1 caused abnormal Ca²⁺ buffering dynamics and reduced the activity of monoamine oxidase A. Thus, the authors present a mechanism by which DISC1 is connected to mitochondrial location and mitochondrial function, providing further evidence that mitochondrial dysfunction can be an important factor in major psychiatric disorders.

References:

Blackwood, D. H., Fordyce, A., Walker, M. T., St Clair, D. M., Porteous, D. J., Muir, W. J., 2001. Schizophrenia and affective disorders--cosegregation with a translocation at chromosome 1q42 that directly disrupts brain-expressed genes: clinical and P300 findings in a family. Am J Hum Genet. 69, 428-33. Abstract

Brandon, N. J., Schurov, I., Camargo, L. M., Handford, E. J., Duran-Jimeniz, B., Hunt, P., Millar, J. K., Porteous, D. J., Shearman, M. S., Whiting, P. J., 2005. Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. Mol Cell Neurosci. 28, 613-24. Abstract

Camargo, L. M., Collura, V., Rain, J. C., Mizuguchi, K., Hermjakob, H., Kerrien, S., Bonnert, T. P., Whiting, P. J., Brandon, N. J., 2007. Disrupted in Schizophrenia 1 Interactome: evidence for the close connectivity of risk genes and a potential synaptic basis for schizophrenia. Mol Psychiatry. 12, 74-86. Abstract

Clay, H. B., Sillivan, S., Konradi, C., 2010. Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int J Dev Neurosci. Abstract

James, R., Adams, R. R., Christie, S., Buchanan, S. R., Porteous, D. J., Millar, J. K., 2004. Disrupted in Schizophrenia 1 (DISC1) is a multicompartmentalized protein that predominantly localizes to mitochondria. Mol Cell Neurosci. 26, 112-22. Abstract

Millar, J. K., James, R., Christie, S., Porteous, D. J., 2005. Disrupted in schizophrenia 1 (DISC1): subcellular targeting and induction of ring mitochondria. Mol Cell Neurosci. 30, 477-84. Abstract

Morris, J. A., Kandpal, G., Ma, L., Austin, C. P., 2003. DISC1 (Disrupted-In-Schizophrenia 1) is a centrosome-associated protein that interacts with MAP1A, MIPT3, ATF4/5 and NUDEL: regulation and loss of interaction with mutation. Hum Mol Genet. 12, 1591-608. Abstract

Park, Y. U., Jeong, J., Lee, H., Mun, J. Y., Kim, J. H., Lee, J. S., Nguyen, M. D., Han, S. S., Suh, P. G., Park, S. K., 2010. Disrupted-in-schizophrenia 1 (DISC1) plays essential roles in mitochondria in collaboration with Mitofilin. Proc Natl Acad Sci U S A. 107, 17785-90. Abstract

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