Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome.
Activity-Dependent Arc Expression and Homeostatic Synaptic Plasticity Are Altered in Neurons from a Mouse Model of Angelman Syndrome.
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DOI：
10.3389/fnmol.2017.00234
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发表时间：
2017
影响因子：
4.8
通讯作者：
Shepherd JD
中科院分区：
文献类型：
--
作者：
Pastuzyn ED;Shepherd JD
Angelman综合征（AS）是一种神经发育障碍，由15号染色体（通常包括UBE 3A基因）的缺失或突变引起。Ube 3A蛋白是一种E3泛素连接酶，其将蛋白质泛素化并靶向它们进行降解。即时早期基因Arc是突触可塑性的主要调节因子，被认为是Ube 3A的底物，但关于Arc是否是真正的E3连接酶底物的报道相互矛盾。使用多种方法，我们没有发现Arc和Ube 3A在体内物理相互作用的证据。尽管如此，活动诱导的Arc亚细胞分布在Ube 3am −/p+小鼠的大脑中发生了改变，突触处的Arc浓度异常。此外，虽然Arc转录的激活是正常的，但在从Ube 3am −/p+小鼠培养的海马神经元树突中，Arc蛋白的稳定性增强。最后，表面AMPA受体的稳态突触缩放在Ube 3am −/p+海马神经元中不发生，这让人想起缺乏Arc蛋白的神经元。虽然Ube 3A似乎并没有在典型的E3连接酶-底物相互作用中结合Arc，但在Ube 3am −/p+小鼠中Arc依赖性突触可塑性仍然改变，这可能是在AS中观察到的认知缺陷的基础。
Angelman syndrome (AS) is a neurodevelopmental disorder that results from deletions or mutations in chromosome 15, which usually includes the UBE3A gene. Ube3A protein is an E3 ubiquitin ligase that ubiquitinates proteins and targets them for degradation. The immediate-early gene Arc, a master regulator of synaptic plasticity, was identified as a putative substrate of Ube3A, but there have been conflicting reports on whether Arc is a bona fide E3 ligase substrate. Using multiple approaches, we found no evidence for a physical interaction between Arc and Ube3A in vivo. Nonetheless, activity-induced subcellular distribution of Arc is altered in brains from Ube3am−/p+ mice, with abnormal concentration of Arc at synapses. Furthermore, although activation of Arc transcription is normal, the stability of Arc protein is enhanced in dendrites of hippocampal neurons cultured from Ube3am−/p+ mice. Finally, homeostatic synaptic scaling of surface AMPA receptors does not occur in Ube3am−/p+ hippocampal neurons, reminiscent of neurons that lack Arc protein. Although Ube3A does not seem to bind Arc in a canonical E3 ligase-substrate interaction, Arc-dependent synaptic plasticity is still altered in Ube3am−/p+ mice, which may underlie the cognitive deficits observed in AS.
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影响因子：
25
作者：
McCurry, Cortina L.;Shepherd, Jason D.;Tropea, Daniela;Wang, Kuan H.;Bear, Mark F.;Sur, Mriganka
通讯作者：
Sur, Mriganka
影响因子：
2.5
作者：
Burette, Alain C.;Judson, Matthew C.;Burette, Susan;Phend, Kristen D.;Philpot, Benjamin D.;Weinberg, Richard J.
通讯作者：
Weinberg, Richard J.
影响因子：
16.2
作者：
Chowdhury, Shoaib;Shepherd, Jason D.;Worley, Paul F.
通讯作者：
Worley, Paul F.
影响因子：
12.4
作者：
Louria-Hayon, I.;Alsheich-Bartok, O.;Haupt, Y.
通讯作者：
Haupt, Y.
影响因子：
64.8
作者：
Huang, Hsien-Sung;Allen, John A.;Mabb, Angela M.;King, Ian F.;Miriyala, Jayalakshmi;Taylor-Blake, Bonnie;Sciaky, Noah;Dutton, J. Walter, Jr.;Lee, Hyeong-Min;Chen, Xin;Jin, Jian;Bridges, Arlene S.;Zylka, Mark J.;Roth, Bryan L.;Philpot, Benjamin D.
通讯作者：
Philpot, Benjamin D.