title: DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway.
abstract: Disrupted-in-Schizophrenia 1 (DISC1) is a susceptibility gene for major mental illnesses, including bipolar disorder and schizophrenia. Although the roles of DISC1 in nervous system development and functions are increasingly recognized, pathophysiological mechanisms underlying a range of neuropsychiatric symptoms caused by DISC1 mutations remain unclear. Here we show that DISC1 enhances synaptic vesicle transport along microtubules. Knocking down DISC1 expression results in attenuated vesicle transport in primary cortical neurons. Likewise, expressing the dominant-negative, breakpoint mutant version of DISC1 causes defective vesicle transport, by disrupting the assembly between the kinesin-1 adaptor FEZ1 and the cargo protein Synaptotagmin-1 (Syt-1). In addition, lithium, a mood-stabilizing agent used for the treatment of bipolar disorder, can restore the assembly of FEZ1 and Syt-1, and normalizes the defective transport caused by the dominant-negative DISC1. Thus, this study addresses a new role of DISC1 in organelle transport in neurons, and suggests that this cellular pathway could be therapeutically targeted for the treatment against neuropsychiatric diseases.
authors.affiliation: Department of Neurosciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Flores
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hirota
authors.forename: Brian
authors.initials: B
authors.lastname: Armstrong
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Tomoda
mesh_terms: D000818:Animals; D001370:Axonal Transport / Q000187:drug effects / Q000502:physiology*; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D018020:Lithium Compounds / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D061251:Primary Cell Culture / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013572:Synaptic Vesicles / Q000187:drug effects / Q000378:metabolism*
chemical_list: C498794:Disc1 protein, mouse; D018020:Lithium Compounds; D009419:Nerve Tissue Proteins