ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.
ASTN2 modulates synaptic strength by trafficking and degradation of surface proteins.
复制标题
DOI：
10.1073/pnas.1809382115
复制
发表时间：
2018-10-09
影响因子：
11.1
通讯作者：
Hatten ME
中科院分区：
文献类型：
--
作者：
Behesti H;Fore TR;Wu P;Horn Z;Leppert M;Hull C;Hatten ME
神经遗传学研究表明，ASTN2基因的拷贝数变异（CNVs）发生在包括自闭症谱系在内的神经发育障碍（ndd）患者中。在这里，我们发现ASTN2与小脑神经元中的循环和降解囊泡相关，并结合并促进突触蛋白的内吞运输和降解。神经元中ASTN2的过表达增加突触活性并降低ASTN2结合伴侣的水平，这一作用依赖于其FNIII结构域，在ndd患者中，该结构域经常被CNVs扰乱。这些发现表明，ASTN2是突触蛋白动态运输的关键调节因子，并支持神经元中蛋白质稳态的异常调节是复杂ndd的一个原因的观点。表面蛋白动力学决定突触连接和功能在神经元回路。ASTN2是一种在神经发育障碍（包括自闭症谱系）中被拷贝数变异（cnv）破坏的基因，先前已被证明在胶质细胞引导的神经元迁移中调节ASTN1的表面表达。在这里，我们证明了ASTN2通过内吞作用结合并调节迁移后神经元中多种突触蛋白的表面表达，从而调节突触活性。在小脑浦肯野细胞（PCs）中，通过免疫金电镜，ASTN2主要定位于细胞体和树突棘亚群中的内吞和自噬细胞囊泡。ASTN2在pc中的过表达，但不包括缺乏FNIII结构域的ASTN2，在患者中反复被cnv破坏，包括在这里提出的一个家族中，增加抑制性和兴奋性突触后活性，降低ASTN2结合伴侣的水平。我们的数据表明，ASTN2在通过内吞运输和蛋白质降解对表面蛋白的动态调节中发挥了重要作用。
Neurogenetic studies demonstrate that copy number variations (CNVs) in the ASTN2 gene occur in patients with neurodevelopmental disorders (NDDs), including autism spectrum. Here, we show that ASTN2 associates with recycling and degradative vesicles in cerebellar neurons, and binds to and promotes the endocytic trafficking and degradation of synaptic proteins. Overexpression of ASTN2 in neurons increases synaptic activity and reduces the levels of ASTN2 binding partners, an effect dependent on its FNIII domain, which is recurrently perturbed by CNVs in patients with NDDs. These findings suggest that ASTN2 is a key regulator of dynamic trafficking of synaptic proteins and lend support to the idea that aberrant regulation of protein homeostasis in neurons is a contributing cause of complex NDDs. Surface protein dynamics dictate synaptic connectivity and function in neuronal circuits. ASTN2, a gene disrupted by copy number variations (CNVs) in neurodevelopmental disorders, including autism spectrum, was previously shown to regulate the surface expression of ASTN1 in glial-guided neuronal migration. Here, we demonstrate that ASTN2 binds to and regulates the surface expression of multiple synaptic proteins in postmigratory neurons by endocytosis, resulting in modulation of synaptic activity. In cerebellar Purkinje cells (PCs), by immunogold electron microscopy, ASTN2 localizes primarily to endocytic and autophagocytic vesicles in the cell soma and in subsets of dendritic spines. Overexpression of ASTN2 in PCs, but not of ASTN2 lacking the FNIII domain, recurrently disrupted by CNVs in patients, including in a family presented here, increases inhibitory and excitatory postsynaptic activity and reduces levels of ASTN2 binding partners. Our data suggest a fundamental role for ASTN2 in dynamic regulation of surface proteins by endocytic trafficking and protein degradation.
登录
查看更多内容
影响因子：
7.7
作者：
Kloth AD;Badura A;Li A;Cherskov A;Connolly SG;Giovannucci A;Bangash MA;Grasselli G;Peñagarikano O;Piochon C;Tsai PT;Geschwind DH;Hansel C;Sahin M;Takumi T;Worley PF;Wang SS
通讯作者：
Wang SS
影响因子：
17.7
作者：
Allen, G;Courchesne, E
通讯作者：
Courchesne, E
影响因子：
25
作者：
Krishnan A;Zhang R;Yao V;Theesfeld CL;Wong AK;Tadych A;Volfovsky N;Packer A;Lash A;Troyanskaya OG
通讯作者：
Troyanskaya OG
影响因子：
3.5
作者：
Fatemi, S. Hossein;Aldinger, Kimberly A.;Ashwood, Paul;Bauman, Margaret L.;Blaha, Charles D.;Blatt, Gene J.;Chauhan, Abha;Chauhan, Ved;Dager, Stephen R.;Dickson, Price E.;Estes, Annette M.;Goldowitz, Dan;Heck, Detlef H.;Kemper, Thomas L.;King, Bryan H.;Martin, Loren A.;Millen, Kathleen J.;Mittleman, Guy;Mosconi, Matthew W.;Persico, Antonio M.;Sweeney, John A.;Webb, Sara J.;Welsh, John P.
通讯作者：
Welsh, John P.
DOI：
10.1111/ejn.12126
发表时间：
2013-04
期刊：
The European journal of neuroscience
影响因子：
--
作者：
Kim JY;Ash RT;Ceballos-Diaz C;Levites Y;Golde TE;Smirnakis SM;Jankowsky JL
通讯作者：
Jankowsky JL