Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.
Rare autism-associated variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter (hDAT R51W) in dopamine neurotransmission and behaviors.
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DOI：
10.1016/j.ebiom.2015.01.007
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发表时间：
2015-02
期刊：
影响因子：
11.1
通讯作者：
Galli, Aurelio
中科院分区：
文献类型：
--
作者：
Cartier, Etienne;Hamilton, Peter J.;Belovich, Andrea N.;Shekar, Aparna;Campbell, Nicholas G.;Saunders, Christine;Andreassen, Thorvald F.;Gether, Ulrik;Veenstra-Vanderweele, Jeremy;Sutcliffe, James S.;Ulery-Reynolds, Paula G.;Erreger, Kevin;Matthies, Heinrich J. G.;Galli, Aurelio
突触蛋白1(Synaxin 1，STX1)是一种协调突触小泡融合的突触前质膜蛋白。STX1还调节神经递质转运体的功能，包括多巴胺(DA)转运体(DAT)。DAT是一种膜蛋白，通过高亲和力重新摄取突触释放的DA来控制DA的动态平衡。我们采用最新发展的动物模型和最先进的生物物理技术来确定已识别的基因变异在自闭症谱系障碍(ASD)中观察到的DA神经传递障碍中的贡献。在这里，我们描述了编码STX1和DAT的基因中两个独立的与自闭症相关的变体。我们演示了每一种变体都显著地改变了DAT功能。我们确定了收敛以抑制DA和DA相关行为的反向运输的分子机制。这些机制包括酪蛋白激酶2介导的Ser14上STX1的磷酸化减少以及STX1/DAT相互作用的减少。这些发现表明，STX1/DAT相互作用和STX1磷酸化是DA动态平衡的关键调节因素。我们确定这些变异的分子同一性和影响，目的是将DA功能障碍和相关行为定义为ASD可能的并发症。我们报告了两个独立的与自闭症相关的突变体，它们分别位于合成素和多巴胺转运体中。合成素和多巴胺转运体的变异都会损害多巴胺的反向运输。多巴胺神经传递的失调可能是自闭症谱系障碍的并发症。
Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt newly developed animal models and state-of-the-art biophysical techniques to determine the contribution of the identified gene variants to impairments in DA neurotransmission observed in autism spectrum disorder (ASD). Here, we characterize two independent autism-associated variants in the genes that encode STX1 and the DAT. We demonstrate that each variant dramatically alters DAT function. We identify molecular mechanisms that converge to inhibit reverse transport of DA and DA-associated behaviors. These mechanisms involve decreased phosphorylation of STX1 at Ser14 mediated by casein kinase 2 as well as a reduction in STX1/DAT interaction. These findings point to STX1/DAT interactions and STX1 phosphorylation as key regulators of DA homeostasis. We determine the molecular identity and the impact of these variants with the intent of defining DA dysfunction and associated behaviors as possible complications of ASD. We report two independent autism-associated variants in syntaxin and the dopamine transporter. The variants in syntaxin and dopamine transporter each impair reverse transport of dopamine. Dysregulation of dopamine neurotransmission may represent a complication of autism spectrum disorder.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
DOI：
10.1523/jneurosci.5094-09.2010
发表时间：
2010-04-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bowton E;Saunders C;Erreger K;Sakrikar D;Matthies HJ;Sen N;Jessen T;Colbran RJ;Caron MG;Javitch JA;Blakely RD;Galli A
通讯作者：
Galli A
影响因子：
5.3
作者：
Kume, K;Kume, S;Jackson, FR
通讯作者：
Jackson, FR
影响因子：
2.6
作者：
Kohls, Gregor;Perino, Michael T.;Taylor, James M.;Madva, Elizabeth N.;Cayless, Sarah J.;Troiani, Vanessa;Price, Elinora;Faja, Susan;Herrington, John D.;Schultz, Robert T.
通讯作者：
Schultz, Robert T.
影响因子：
4.7
作者：
Kohls G;Thönessen H;Bartley GK;Grossheinrich N;Fink GR;Herpertz-Dahlmann B;Konrad K
通讯作者：
Konrad K