TY - JOUR
T1 - DISC1 regulates synaptic vesicle transport via a lithium-sensitive pathway
AU - Flores, Rafael
AU - Hirota, Yuki
AU - Armstrong, Brian
AU - Sawa, Akira
AU - Tomoda, Toshifumi
N1 - Funding Information:
We thank Joseph Gogos for the N-terminal DISC1 antibody, Michael Barish and Keely Walker for comments and reading the manuscript, Fred Saudou, Sandrine Humbert, Diana Zala, and members of the Sawa lab for discussion. Supported by USPHS grants of MH-084018 Silvo O. Conte center (A.S.), MH-069853 (A.S.), MH-085226 (A.S.), MH-088753 (A.S.), grants from Stanley and RUSK foundations , NARSAD , S-R foundations , and Maryland Stem Cell Research Fund (A.S.), and DOD/CDMRP-W81XWH-11-1-0269 (T.T.).
PY - 2011/9
Y1 - 2011/9
N2 - 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.
AB - 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.
KW - Bipolar disorder
KW - DISC1
KW - FEZ1
KW - Lithium
KW - Motor-cargo assembly
KW - Vesicle transport
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U2 - 10.1016/j.neures.2011.05.014
DO - 10.1016/j.neures.2011.05.014
M3 - Article
C2 - 21664390
AN - SCOPUS:79960916466
SN - 0168-0102
VL - 71
SP - 71
EP - 77
JO - Neuroscience Research
JF - Neuroscience Research
IS - 1
ER -