Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.
Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.
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DOI：
10.1038/s41467-023-39337-0
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发表时间：
2023-06-26
影响因子：
16.6
通讯作者：
Doherty, Dan
中科院分区：
文献类型：
--
作者：
Guo, Yu;Shen, Minjie;Dong, Qiping;Mendez-Albelo, Natasha M.;Huang, Sabrina X.;Sirois, Carissa L.;Le, Jonathan;Li, Meng;Jarzembowski, Ezra D.;Schoeller, Keegan A.;Stockton, Michael E.;Horner, Vanessa L.;Sousa, Andre M. M.;Gao, Yu;Levine, Jon E.;Wang, Daifeng;Chang, Qiang;Zhao, Xinyu;Glass, Ian A.;Doherty, Dan
脆性X信使核糖核蛋白1蛋白（FMRP）结合脑中的许多mRNA靶点。这些靶点对脆性X综合征（FXS）和相关自闭症谱系障碍（ASD）的贡献仍不清楚。在这里，我们表明，FMRP缺乏导致微管相关蛋白1B（MAP1B）在开发人类和非人类灵长类动物皮层神经元升高。健康人神经元中的靶向MAP1B基因激活或ASD患者源性神经元中的MAP1B基因三重化抑制形态和生理成熟。Map1b在成年雄性小鼠前额叶皮层兴奋性神经元中的激活损害社会行为。我们发现，升高的MAP1B隔离自噬的成分，减少自噬体的形成。MAP1B敲低和自噬激活都挽救了离体人脑组织中ASD和FXS患者神经元和FMRP缺陷神经元的缺陷。我们的研究证明了灵长类神经元中MAP1B的保守FMRP调节，并建立了MAP1B升高与FXS和ASD缺陷之间的因果关系。MAP1B受脆性X蛋白FMRP的结合和调节。在这里，作者表明，MAP1B水平升高会降低人类神经元的形态和生理成熟，并损害小鼠的社会行为。
Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients’ neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD. MAP1B is bound and regulated by fragile X protein FMRP. Here, the authors show that elevated levels of MAP1B reduce the morphological and physiological maturation of human neurons and impair social behavior in mice.
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影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
3.4
作者：
Graef, John D.;Wu, Hao;Wallace, Owen
通讯作者：
Wallace, Owen
DOI：
10.1111/j.1530-0277.2012.01758.x
发表时间：
2012-09
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Lin P;Hartz SM;Wang JC;Agrawal A;Zhang TX;McKenna N;Bucholz K;Brooks AI;Tischfield JA;Edenberg HJ;Hesselbrock VM;Kramer JR;Kuperman S;Schuckit MA;Goate AM;Bierut LJ;Rice JP;COGA Collaborators;COGEND Collaborators, GENEVA
通讯作者：
COGEND Collaborators, GENEVA
DOI：
10.1073/pnas.93.3.1270
发表时间：
1996-02-06
影响因子：
11.1
作者：
Edelmann, W;Zervas, M;Kucherlapati, R
通讯作者：
Kucherlapati, R
影响因子：
2.5
作者：
Gibson, Jay R.;Bartley, Aundrea F.;Huber, Kimberly M.
通讯作者：
Huber, Kimberly M.