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Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons

Molecular Psychiatry volume 16, pages 122–124 (2011)Cite this article

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Disrupted in Schizophrenia-1 (DISC1) has emerged as a leading candidate susceptibility gene for schizophrenia and major mental illness. Growing evidence supports a role for the DISC1 protein in brain development and synaptic function, but the molecular mechanisms underlying this role remain poorly understood.1 Correct neuronal development and function are highly dependent on brain energy supplied in the form of adenosine triphosphate by mitochondria. These organelles are crucial for fuelling essential processes, including axon guidance, neurite outgrowth, synaptogenesis and synaptic and action potential signaling, whereas their dysfunction has been linked to schizophrenia, bipolar disorder and depression.2, 3 Mitochondria are highly dynamic organelles that must be correctly transported by microtubule motor proteins to distant sites in neurons with high energy demand, such as growth cones and pre- and postsynaptic domains.2 Disruption of this transport impairs correct neuronal development, synaptogenesis and synaptic function.2 Although DISC1 has been linked to microtubule transport processes4 and localized to mitochondria,5 whether DISC1 or its disease-associated variants are important in regulating the correct distribution and transport of this essential organelle remains unknown.

Two non-synonymous single-nucleotide polymorphism variants of DISC1, Ser704Cys and Leu607Phe, associate with schizophrenia, bipolar disorder and major depression and have been linked to differences in synaptic function and brain maturation.1, 8, 9, 10 We used shRNAi knockdown of DISC1 combined with coexpression of DISC1 variants resistant to the shRNAi to replace endogenous DISC1 with these variants and address whether the disease-associated polymorphisms influence mitochondrial trafficking. In neurons expressing shRNAi to knock down DISC1, both the common variant (which encodes Leu607/Ser704) and the Cys704 variant could equally rescue mitochondrial trafficking, suggesting no difference in these variants in regulating mitochondrial transport. In contrast, compared with the DISC1 common variant, the Phe607 DISC1 variant was unable to correctly rescue mitochondrial movement in DISC1 RNAi-expressing cells (28.78±2.7% for DISC1 common variant rescue compared with 20.63±2.5% for Phe607 rescue, P=0.047; Figure 1f and g). These results suggest that correct mitochondrial trafficking in neurons expressing the DISC1 Phe607 variant is significantly impaired.

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Authors and Affiliations

  1. Department of Neuroscience, Physiology, and Pharmacology, University College London, London, UK

    T A Atkin, A F MacAskill & J T Kittler

  2. Pfizer Global Research and Development, Neuroscience Research Unit, Groton, CT, USA

    N J Brandon

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  1. T A Atkin
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  2. A F MacAskill
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  3. N J Brandon
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  4. J T Kittler
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Correspondence to J T Kittler.

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Atkin, T., MacAskill, A., Brandon, N. et al. Disrupted in Schizophrenia-1 regulates intracellular trafficking of mitochondria in neurons. Mol Psychiatry 16, 122–124 (2011). https://doi.org/10.1038/mp.2010.110

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