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Axonal Transport and Cytoskeleton

開催日 2014/9/13
時間 14:00 - 15:00
会場 Poster / Exhibition(Event Hall B)

JSAP1 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

  • P3-018
  • 佐藤 時春 / Tokiharu Sato:1 大倉 正道 / Masamichi Ohkura:2 中井 淳一 / Junichi Nakai:2 高松 信彦 / Nobuhiko Takamatsu:3 善岡 克次 / Katsuji Yoshioka:1 
  • 1:金沢大・がん進展制御研究所 / Cancer Research Institute, Kanazawa University, Japan 2:埼玉大・脳末梢科学研究センター / Brain Science Institute, Saitama University, Japan 3:北里大・理 / School of Science, Kitasato University, Japan 

Axonal transport is essential for neuronal development and function, and disrupted axonal transport is an important pathophysiological factor in a variety of neurodegenerative diseases. However, the molecular mechanisms that regulate axonal transport, and how disruption of that transport leads to neuronal degeneration, are poorly understood. Here, we report that c-Jun NH2-terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1) 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 due to increased intra-axonal Ca2+ in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca2+-dependent protease calpain. Our results indicate that axonal JNK relocates 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.

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