香港第一位“女性诺贝尔奖”得主、科技大学新任理学院院长叶玉如，最近在分子神经方面的研究再度取得骄人成绩，成功地解开了脑部神经信号传递之谜，协助延缓患者的认知衰退。两项原创性科研成果，今年分别刊载于 Nature Neuroscience 及 Neuron 两份神经科学界最具权威性的学术期刊上。
人类的认知功能、包括记忆形成的过程，极依赖于神经系统的可塑性，即神经细胞会根据经验，对自身功能进行调节，但当中神经信号传导的分子机理，对科学界而言仍是个未解之谜。
叶玉如与其研究队伍，成功发现一种名为EphA4的细胞，其表面受体就是调控脑部可塑性的关键蛋白，这种蛋白能透过控制神经递质受体的表达量，调节大脑信号传导的活性。其实许多神经退化性疾病，均与脑部神经传导功能障碍有关。叶玉如根据其研究结果提出，EphA4可以成为研发相关药物的新靶点，对医治与认知能力衰退有关的疾病如脑退化症，相信可带来一大突破。
同时，根据其研究结果，EphA4下游的信号蛋白，能够调控神经传导的效率，对维持肌肉力量和运动功能均起关键作用。运动神经与肌肉之间的通讯功能缺陷，正是肌肉萎缩症等神经肌肉疾病的重要致病因素，故其新发现亦为这类疾病的医疗带来新希望。
科大校长陈繁昌对叶玉如及其研究队伍的突破性研究表示振奋，并认为其科研成果对于治疗神经退化性疾病与神经肌肉疾病有重大意义。（生物谷Bioon.com）
生物谷推荐原文出处：
Nature Neuroscience doi:10.1038/nn.2715
APCCdh1 mediates EphA4-dependent downregulation of AMPA receptors in homeostatic plasticity
Amy K Y Fu,Kwok-Wang Hung,Wing-Yu Fu,Chong Shen,Yu Chen,Jun Xia,Kwok-On Lai& Nancy Y Ip
Homeostatic plasticity is crucial for maintaining neuronal output by counteracting unrestrained changes in synaptic strength. Chronic elevation of synaptic activity by bicuculline reduces the amplitude of miniature excitatory postsynaptic currents (mEPSCs), but the underlying mechanisms of this effect remain unclear. We found that activation of EphA4 resulted in a decrease in synaptic and surface GluR1 and attenuated mEPSC amplitude through a degradation pathway that requires the ubiquitin proteasome system (UPS). Elevated synaptic activity resulted in increased tyrosine phosphorylation of EphA4, which associated with the ubiquitin ligase anaphase-promoting complex (APC) and its activator Cdh1 in neurons in a ligand-dependent manner. APCCdh1 interacted with and targeted GluR1 for proteasomal degradation in vitro, whereas depletion of Cdh1 in neurons abolished the EphA4-dependent downregulation of GluR1. Knockdown of EphA4 or Cdh1 prevented the reduction in mEPSC amplitude in neurons that was a result of chronic elevated activity. Our results define a mechanism by which EphA4 regulates homeostatic plasticity through an APCCdh1-dependent degradation pathway.
Neuron doi:10.1016/j.neuron.2010.01.012
Ephexin1 Is Required for Structural Maturation and Neurotransmission at the Neuromuscular Junction
Authors
Lei Shi, Busma Butt, Fanny C.F. Ip, Ying Dai, Liwen Jiang, Wing-Ho Yung, Michael E. Greenberg, Amy K.Y. Fu, Nancy Y. Ip
Highlights
Ephexin1 is essential for synaptic transmission and muscle function at NMJs
Ephexin1 is required for the topological transformation of AChR clusters
Ephexin1 regulates the stability of AChR clusters through activation of RhoA
Ephexin1 directs synapse maturation and maintenance in a RhoA-dependent manner
Summary
The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the presynaptic and postsynaptic specializations. However, little is known about the molecular mechanisms underlying the plaque-to-pretzel transition of AChR clusters. In this study, we identify an essential role for the RhoGEF ephexin1 in the maturation of AChR clusters. Adult ephexin1/ mice exhibit severe muscle weakness and impaired synaptic transmission at the NMJ. Intriguingly, when ephexin1 expression is deficient in vivo, the NMJ fails to mature into the pretzel-like shape, and such abnormalities can be rescued by re-expression of ephexin1. We further demonstrate that ephexin1 regulates the stability of AChR clusters in a RhoA-dependent manner. Taken together, our findings reveal an indispensible role for ephexin1 in regulating the structural maturation and neurotransmission of NMJs.
