Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex.
Activation of Rheb, but not of mTORC1, impairs spine synapse morphogenesis in tuberous sclerosis complex.
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DOI：
10.1038/srep05155
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发表时间：
2014-06-03
影响因子：
4.6
通讯作者：
Yamagata K
中科院分区：
文献类型：
--
作者：
Yasuda S;Sugiura H;Katsurabayashi S;Shimada T;Tanaka H;Takasaki K;Iwasaki K;Kobayashi T;Hino O;Yamagata K
Tsc 1或Tsc 2基因突变导致结节性硬化症（TSC）。Tsc 1和Tsc 2蛋白形成复合物，通过Rheb-GTdR抑制雷帕霉素复合物1（mTORC 1）信号传导的哺乳动物靶标。我们发现Tsc 2 +/−神经元表现出受损的脊柱突触形成，这对mTORC 1抑制剂具有抗性。mTOR的敲除也未能恢复这些异常，表明mTORC可能不参与Tsc 2 +/−神经元中受损的脊髓发生。为了解决Rheb激活是否会损害棘突触形成，我们分别在WT和Tsc 2 +/−神经元中表达了Rheb的活性和非活性形式。活性Rheb的表达消除了WT神经元中树突棘的形成，而非活性Rheb恢复了Tsc 2 +/−神经元中棘突触的形成。此外，用法尼基转移酶抑制剂灭活Rheb恢复了Tsc 2 +/−神经元的棘突触形态发生。总之，TSC神经元树突棘异常可能是通过Rheb的激活引起的，而不是通过mTORC 1。
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.
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影响因子：
16
作者：
Gao D;Inuzuka H;Tan MK;Fukushima H;Locasale JW;Liu P;Wan L;Zhai B;Chin YR;Shaik S;Lyssiotis CA;Gygi SP;Toker A;Cantley LC;Asara JM;Harper JW;Wei W
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作者：
Tavazoie, SF;Alvarez, VA;Sabatini, BL
通讯作者：
Sabatini, BL
影响因子：
64.8
作者：
Possemato, Richard;Marks, Kevin M.;Shaul, Yoav D.;Pacold, Michael E.;Kim, Dohoon;Birsoy, Kivanc;Sethumadhavan, Shalini;Woo, Hin-Koon;Jang, Hyun G.;Jha, Abhishek K.;Chen, Walter W.;Barrett, Francesca G.;Stransky, Nicolas;Tsun, Zhi-Yang;Cowley, Glenn S.;Barretina, Jordi;Kalaany, Nada Y.;Hsu, Peggy P.;Ottina, Kathleen;Chan, Albert M.;Yuan, Bingbing;Garraway, Levi A.;Root, David E.;Mino-Kenudson, Mari;Brachtel, Elena F.;Driggers, Edward M.;Sabatini, David M.
通讯作者：
Sabatini, David M.