title: JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration.
abstract: Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca(2+) in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca(2+)-dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Sato
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ishikawa
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mochizuki
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohta
authors.affiliation: Brain Science Institute, Saitama University, Saitama, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ohkura
authors.affiliation: Brain Science Institute, Saitama University, Saitama, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Nakai
authors.affiliation: Department of Biosciences, School of Science, Kitasato University, Sagamihara, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Takamatsu
authors.affiliation: Division of Molecular Cell Signaling, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yoshioka
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D001369:Axons / Q000378:metabolism* / Q000502:physiology; D002478:Cells, Cultured; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C403619:Mapk8ip3 protein, mouse; D009419:Nerve Tissue Proteins; C468928:Spag9 protein, mouse; D016547:Kinesins