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Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex

Author

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  • Hiroko Sugiura

    (Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science)

  • Shin Yasuda

    (Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science)

  • Shutaro Katsurabayashi

    (Faculty of Pharmaceutical Sciences, Fukuoka University)

  • Hiroyuki Kawano

    (Faculty of Pharmaceutical Sciences, Fukuoka University)

  • Kentaro Endo

    (Center of Basic Technology Research, Tokyo Metropolitan Institute of Medical Science)

  • Kotaro Takasaki

    (Faculty of Pharmaceutical Sciences, Fukuoka University)

  • Katsunori Iwasaki

    (Faculty of Pharmaceutical Sciences, Fukuoka University)

  • Masumi Ichikawa

    (Center of Basic Technology Research, Tokyo Metropolitan Institute of Medical Science)

  • Toshiyuki Kobayashi

    (Juntendo University, School of Medicine)

  • Okio Hino

    (Juntendo University, School of Medicine)

  • Kanato Yamagata

    (Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science)

Abstract

Rheb is a small GTP-binding protein and its GTPase activity is activated by the complex of Tsc1 and Tsc2 whose mutations cause tuberous sclerosis complex (TSC). We previously reported that cultured TSC neurons showed impaired spine synapse morphogenesis in an mTORC1-independent manner. Here we show that the PDZ protein syntenin preferentially binds to the GDP-bound form of Rheb. The levels of syntenin are significantly higher in TSC neurons than in wild-type neurons because the Rheb-GDP-syntenin complex is prone to proteasomal degradation. Accumulated syntenin in TSC neurons disrupts spine synapse formation through inhibition of the association between syndecan-2 and calcium/calmodulin-dependent serine protein kinase. Instead, syntenin enhances excitatory shaft synapse formation on dendrites by interacting with ephrinB3. Downregulation of syntenin in TSC neurons restores both spine and shaft synapse densities. These findings suggest that Rheb-syntenin signalling may be a novel therapeutic target for abnormalities in spine and shaft synapses in TSC neurons.

Suggested Citation

  • Hiroko Sugiura & Shin Yasuda & Shutaro Katsurabayashi & Hiroyuki Kawano & Kentaro Endo & Kotaro Takasaki & Katsunori Iwasaki & Masumi Ichikawa & Toshiyuki Kobayashi & Okio Hino & Kanato Yamagata, 2015. "Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex," Nature Communications, Nature, vol. 6(1), pages 1-15, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms7842
    DOI: 10.1038/ncomms7842
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