title: DISC1-dependent Regulation of Mitochondrial Dynamics Controls the Morphogenesis of Complex Neuronal Dendrites.
abstract: The DISC1 protein is implicated in major mental illnesses including schizophrenia, depression, bipolar disorder, and autism. Aberrant mitochondrial dynamics are also associated with major mental illness. DISC1 plays a role in mitochondrial transport in neuronal axons, but its effects in dendrites have yet to be studied. Further, the mechanisms of this regulation and its role in neuronal development and brain function are poorly understood. Here we have demonstrated that DISC1 couples to the mitochondrial transport and fusion machinery via interaction with the outer mitochondrial membrane GTPase proteins Miro1 and Miro2, the TRAK1 and TRAK2 mitochondrial trafficking adaptors, and the mitochondrial fusion proteins (mitofusins). Using live cell imaging, we show that disruption of the DISC1-Miro-TRAK complex inhibits mitochondrial transport in neurons. We also show that the fusion protein generated from the originally described DISC1 translocation (DISC1-Boymaw) localizes to the mitochondria, where it similarly disrupts mitochondrial dynamics. We also show by super resolution microscopy that DISC1 is localized to endoplasmic reticulum contact sites and that the DISC1-Boymaw fusion protein decreases the endoplasmic reticulum-mitochondria contact area. Moreover, disruption of mitochondrial dynamics by targeting the DISC1-Miro-TRAK complex or upon expression of the DISC1-Boymaw fusion protein impairs the correct development of neuronal dendrites. Thus, DISC1 acts as an important regulator of mitochondrial dynamics in both axons and dendrites to mediate the transport, fusion, and cross-talk of these organelles, and pathological DISC1 isoforms disrupt this critical function leading to abnormal neuronal development.
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Rosalind
authors.initials: R
authors.lastname: Norkett
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Souvik
authors.initials: S
authors.lastname: Modi
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Nicol
authors.initials: N
authors.lastname: Birsa
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Talia A
authors.initials: TA
authors.lastname: Atkin
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Davor
authors.initials: D
authors.lastname: Ivankovic
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom.
authors.forename: Manav
authors.initials: M
authors.lastname: Pathania
authors.affiliation: the Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225 Dusseldorf, Germany.
authors.forename: Svenja V
authors.initials: SV
authors.lastname: Trossbach
authors.affiliation: the Department of Neuropathology, Heinrich Heine University, Moorenstrasse 5, 40225 Dusseldorf, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Korth
authors.affiliation: the Neuroscience Research Unit, Pfizer, Cambridge, Massachusetts 02139, and.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.affiliation: From the Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom, j.kittler@ucl.ac.uk.
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D001692:Biological Transport; D019556:COS Cells; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D009024:Morphogenesis; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D062085:RNA, Long Noncoding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012559:Schizophrenia / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C412476:DISC1 protein, human; C552845:DISC1FP1 non-coding RNA, human; D033681:Mitochondrial Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D062085:RNA, Long Noncoding; D011993:Recombinant Fusion Proteins
keywords: DISC1; DISC1-Boymaw fusion protein; Miro; dendrite; endoplasmic reticulum (ER); mitochondria; mitofusin; schizophrenia; trafficking