title: Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport.
abstract: Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11-amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Chiba
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Araseki
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nozawa
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Keiko
authors.initials: K
authors.lastname: Furukori
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Araki
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Matsushima
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nakaya
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Hata
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Human Interface Laboratory, Department of Advanced Information Technology, Faculty of Information Sciences and Electrical Engineering, Kyushu University, Fukuoka 819-0395, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Uchida
authors.affiliation: Laboratory for Cell Polarity Regulation, RIKEN Quantitative Biology Center, Suita 565-0874, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508.
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.affiliation: Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Department of Molecular Neurobiology, Faculty of Medicine, Kagawa University, Miki-cho 761-0793, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Laboratory of Molecular Cell Dynamics, Faculty of Advanced Life Science, Hokkaido University, Sapporo 001-0021, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Kinjo
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Taru
authors.affiliation: Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan tsuzuki@pharm.hokudai.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000235:genetics*; D019556:COS Cells; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids; D061251:Primary Cell Culture; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D015398:Signal Transduction; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C000715688:KLC1 protein, human; C000715695:Kns2 protein, mouse; C490665:Mapk8ip protein, mouse; D008869:Microtubule-Associated Proteins; D048670:MAP Kinase Kinase 4; C475469:Kif5b protein, mouse; D016547:Kinesins