Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
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DOI：
10.1038/ncomms7842
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发表时间：
2015-04
影响因子：
16.6
通讯作者：
H. Sugiura;Shin Yasuda;S. Katsurabayashi;Hiroyuki Kawano;Kentaro Endo;Kotaro Takasaki;K. Iwasaki;M. Ichikawa;Toshiyuki Kobayashi;O. Hino;K. Yamagata
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文献类型：
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作者：
H. Sugiura;Shin Yasuda;S. Katsurabayashi;Hiroyuki Kawano;Kentaro Endo;Kotaro Takasaki;K. Iwasaki;M. Ichikawa;Toshiyuki Kobayashi;O. Hino;K. Yamagata
Rheb是一种小的GTP结合蛋白，其GTP酶活性被Tsc 1和Tsc 2的复合物激活，Tsc 1和Tsc 2的突变导致结节性硬化症复合物（TSC）。我们以前报道，培养的TSC神经元表现出受损的脊髓突触形态发生在mTORC 1独立的方式。在这里，我们表明，PDZ蛋白syntenin优先结合的GDP结合形式的Rheb。TSC神经元中syntenin的水平显著高于野生型神经元，因为Rheb-GDP-syntenin复合物易于蛋白酶体降解。TSC神经元中积累的syntenin通过抑制syndecan-2和钙/钙调蛋白依赖性丝氨酸蛋白激酶之间的关联来破坏脊柱突触形成。相反，syntenin通过与ephrinB 3相互作用增强树突上兴奋性轴突触的形成。TSC神经元中突触蛋白的下调恢复了棘和轴突触密度。这些研究结果表明，Rheb-syntenin信号转导可能是一种新的治疗靶点，在TSC神经元的脊柱和轴突触异常。
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.