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DISC1 complexes with TRAK1 and Miro1 to modulate anterograde axonal mitochondrial trafficking

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    Rights statement: Copyright © The Author 2013. Published by Oxford University Press This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

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http://hmg.oxfordjournals.org/content/early/2013/10/16/hmg.ddt485
Original languageEnglish
JournalHuman Molecular Genetics
DOIs
Publication statusPublished - 2 Oct 2013

Abstract

DISC1 is a candidate risk factor for schizophrenia, bipolar disorder and severe recurrent depression. Here we demonstrate that DISC1 associates robustly with TRAK1 which is, in turn, known to interact with the outer mitochondrial membrane proteins Miro1/2, linking mitochondria to the kinesin motor for microtubule-based subcellular trafficking. DISC1 also associates with Miro1 and is thus a component of functional mitochondrial transport complexes. Consistent with these observations, in neuronal axons DISC1 promotes specifically anterograde mitochondrial transport. DISC1 thus participates directly in mitochondrial trafficking, which is essential for neural development and neurotransmission. Any factor affecting mitochondrial DISC1 function is hence likely to have deleterious consequences for the brain, potentially contributing to increased risk of psychiatric illness. Intriguingly, therefore, a rare putatively causal human DISC1 sequence variant, 37 W, impairs the ability of DISC1 to promote anterograde mitochondrial transport. This is likely related to a number of mitochondrial abnormalities induced by expression of DISC1-37 W, which redistributes mitochondrial DISC1 and enhances kinesin mitochondrial association, while also altering protein interactions within the mitochondrial transport complex.

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