在结节性硬化症中，Rheb的激活而非mTORC1的激活会损害脊柱突触形态发生。
Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex.
作者信息
Yasuda Shin, Sugiura Hiroko, Katsurabayashi Shutaro, Shimada Tadayuki, Tanaka Hidekazu, Takasaki Kotaro, Iwasaki Katsunori, Kobayashi Toshiyuki, Hino Okio, Yamagata Kanato
机构信息
1] Neural Plasticity Project, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan [2].
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
出版信息
Sci Rep. 2014 Jun 3;4:5155. doi: 10.1038/srep05155.
Mutations in the Tsc1 or Tsc2 genes cause tuberous sclerosis complex (TSC). Tsc1 and Tsc2 proteins form a complex that inhibits mammalian target of rapamycin complex 1 (mTORC1) signalling through Rheb-GTPase. We found that Tsc2(+/-) neurons showed impaired spine synapse formation, which was resistant to an mTORC1 inhibitor. Knockdown of mTOR also failed to restore these abnormalities, suggesting mTORC may not participate in impaired spinogenesis in Tsc2(+/-) neurons. To address whether Rheb activation impairs spine synapse formation, we expressed active and inactive forms of Rheb in WT and Tsc2(+/-) neurons, respectively. Expression of active Rheb abolished dendritic spine formation in WT neurons, whereas inactive Rheb restored spine synapse formation in Tsc2(+/-) neurons. Moreover, inactivation of Rheb with farnesyl transferase inhibitors recovered spine synapse morphogenesis in Tsc2(+/-) neurons. In conclusion, dendritic spine abnormalities in TSC neurons may be caused through activation of Rheb, but not through of mTORC1.
Tsc1或Tsc2基因的突变会导致结节性硬化症（TSC）。Tsc1和Tsc2蛋白形成一个复合物，通过Rheb - GTP酶抑制雷帕霉素复合物1（mTORC1）信号传导。我们发现Tsc2(+/-)神经元的脊柱突触形成受损，且对mTORC1抑制剂有抗性。敲低mTOR也未能恢复这些异常，这表明mTORC可能不参与Tsc2(+/-)神经元中受损的脊柱发生过程。为了探究Rheb激活是否会损害脊柱突触形成，我们分别在野生型（WT）和Tsc2(+/-)神经元中表达了活性和非活性形式的Rheb。活性Rheb的表达消除了WT神经元中的树突棘形成，而非活性Rheb恢复了Tsc2(+/-)神经元中的脊柱突触形成。此外，法尼基转移酶抑制剂使Rheb失活可恢复Tsc2(+/-)神经元中的脊柱突触形态发生。总之，TSC神经元中的树突棘异常可能是由Rheb激活引起的，而非mTORC1激活。
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