香港第一位“女性諾貝爾獎”得主,、科技大學(xué)新任理學(xué)院院長葉玉如,，最近在分子神經(jīng)方面的研究再度取得驕人成績，成功地解開了腦部神經(jīng)信號傳遞之謎,，協(xié)助延緩患者的認(rèn)知衰退,。兩項原創(chuàng)性科研成果，今年分別刊載于 Nature Neuroscience 及 Neuron 兩份神經(jīng)科學(xué)界最具權(quán)威性的學(xué)術(shù)期刊上,。
人類的認(rèn)知功能,、包括記憶形成的過程，極依賴于神經(jīng)系統(tǒng)的可塑性,，即神經(jīng)細(xì)胞會根據(jù)經(jīng)驗,，對自身功能進(jìn)行調(diào)節(jié)，但當(dāng)中神經(jīng)信號傳導(dǎo)的分子機理，對科學(xué)界而言仍是個未解之謎,。
葉玉如與其研究隊伍,，成功發(fā)現(xiàn)一種名為EphA4的細(xì)胞，其表面受體就是調(diào)控腦部可塑性的關(guān)鍵蛋白,，這種蛋白能透過控制神經(jīng)遞質(zhì)受體的表達(dá)量,，調(diào)節(jié)大腦信號傳導(dǎo)的活性。其實許多神經(jīng)退化性疾病,，均與腦部神經(jīng)傳導(dǎo)功能障礙有關(guān),。葉玉如根據(jù)其研究結(jié)果提出，EphA4可以成為研發(fā)相關(guān)藥物的新靶點,，對醫(yī)治與認(rèn)知能力衰退有關(guān)的疾病如腦退化癥,，相信可帶來一大突破。
同時,，根據(jù)其研究結(jié)果,，EphA4下游的信號蛋白，能夠調(diào)控神經(jīng)傳導(dǎo)的效率,，對維持肌肉力量和運動功能均起關(guān)鍵作用,。運動神經(jīng)與肌肉之間的通訊功能缺陷，正是肌肉萎縮癥等神經(jīng)肌肉疾病的重要致病因素,，故其新發(fā)現(xiàn)亦為這類疾病的醫(yī)療帶來新希望,。
科大校長陳繁昌對葉玉如及其研究隊伍的突破性研究表示振奮，并認(rèn)為其科研成果對于治療神經(jīng)退化性疾病與神經(jīng)肌肉疾病有重大意義,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
