title: NDE1 and GSK3β Associate with TRAK1 and Regulate Axonal Mitochondrial Motility: Identification of Cyclic AMP as a Novel Modulator of Axonal Mitochondrial Trafficking.
abstract: Mitochondria are essential for neuronal function, providing the energy required to power neurotransmission, and fulfilling many important additional roles. In neurons, mitochondria must be efficiently transported to sites, including synapses, where their functions are required. Neurons, with their highly elongated morphology, are consequently extremely sensitive to defective mitochondrial trafficking which can lead to neuronal ill-health/death. We recently demonstrated that DISC1 associates with mitochondrial trafficking complexes where it associates with the core kinesin and dynein adaptor molecule TRAK1. We now show that the DISC1 interactors NDE1 and GSK3β also associate robustly with TRAK1 and demonstrate that NDE1 promotes retrograde axonal mitochondrial movement. GSK3β is known to modulate axonal mitochondrial motility, although reports of its actual effect are conflicting. We show that, in our system, GSK3β promotes anterograde mitochondrial transport. Finally, we investigated the influence of cAMP elevation upon mitochondrial motility, and found a striking increase in mitochondrial motility and retrograde movement. DISC1, NDE1, and GSK3β are implicated as risk factors for major mental illness. Our demonstration that they function together within mitochondrial trafficking complexes suggests that defective mitochondrial transport may be a contributory disease mechanism in some cases of psychiatric disorder.
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ogawa
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Murphy
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Elise L V
authors.initials: EL
authors.lastname: Malavasi
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Shane T
authors.initials: ST
authors.lastname: O'Sullivan
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: Helen S
authors.initials: HS
authors.lastname: Torrance
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: University of Edinburgh Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine , Crewe Road, Edinburgh, EH4 2XU, United Kingdom.
authors.forename: J Kirsty
authors.initials: JK
authors.lastname: Millar
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D019556:COS Cells; D002352:Carrier Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000502:physiology*; D055785:Gene Knockdown Techniques / Q000379:methods; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins; D008928:Mitochondria / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D021381:Protein Transport / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D008869:Microtubule-Associated Proteins; C531336:Nde1 protein, mouse; C509169:Trak1 protein, mouse; D000242:Cyclic AMP; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse
keywords: GSK3β: DISC1; Mitochondrial trafficking; NDE1; TRAK1; cAMP