酯酰輔酶A合成酶長鏈家族成員4（ACSL4）是脂代謝中一個重要的酶,，它催化長鏈脂肪酸和輔酶A反應(yīng)生成酯酰輔酶A,。這個步驟使長鏈脂肪酸活化而進(jìn)入脂類合成和能量代謝。因此,，ACSL4對于許多代謝途徑和信號途徑都是必須的,。這個基因的突變可導(dǎo)致智力發(fā)育遲滯(mental retardation)，但其發(fā)病機(jī)制還遠(yuǎn)不清楚。
中科院遺傳與發(fā)育生物學(xué)研究所王朝暉研究組最先建立了該疾病的果蠅模型（Zhang et al., Hum Mol Genet, 2009）,。在最新研究中,，該所張永清研究組利用這個模型，進(jìn)一步在果蠅的神經(jīng)肌肉系統(tǒng)中分析了該基因的功能,。他們發(fā)現(xiàn),，dAcsl突變體的運(yùn)動神經(jīng)元軸突中存在大量突觸囊泡蛋白的聚集，而線粒體和細(xì)胞粘連分子Fasciclin II在軸突中的分布卻沒有變化,。結(jié)合免疫染色和電鏡,，他們確定這些聚集物主要是晚期胞內(nèi)體（late endosome）/溶酶體（lysosome）以及多囊泡結(jié)構(gòu)（Multivesicular bodies）等。而這些結(jié)構(gòu)被認(rèn)為是反向軸突運(yùn)輸?shù)呢浳?，提示dAcsl突變體中反向軸突運(yùn)輸可能受損,。
利用活體成像的方法，研究人員進(jìn)一步直接觀察到突變體中用GFP標(biāo)記的囊泡的反向運(yùn)輸速度,、流量以及運(yùn)動的連續(xù)性受損,，而正向運(yùn)輸?shù)乃俣壬杂屑涌臁０殡S反向運(yùn)輸缺陷,，他們發(fā)現(xiàn)突變體軸突較長的運(yùn)動神經(jīng)元突觸萎縮并在發(fā)育過程中回縮,，且這些突觸的電活動傳導(dǎo)也減弱。這些結(jié)果說明,，dAcsl參與調(diào)控軸突的囊泡運(yùn)輸和突觸發(fā)育,。尤為重要的是，果蠅dAcsl突變體在神經(jīng)系統(tǒng)的表型都可通過表達(dá)人類ACSL4所挽救,，說明人類ACSL4和果蠅dAcsl的功能在進(jìn)化上高度保守,。
這些發(fā)現(xiàn)對ACSL4突變?nèi)绾螌?dǎo)致智力發(fā)育遲滯的分子機(jī)制提供了全新的見解，也為將來治療或緩解病人的腦功能障礙提供了理論基礎(chǔ),。該研究發(fā)表于2011年2月The Journal of Neuroscience雜志。張永清實(shí)驗(yàn)室研究生劉志華為該論文第一作者,。
該項(xiàng)目得到國家自然科學(xué)基金和科技部的資助,。（生物谷Bioon.com）
生物谷推薦原文出處：
The Journal of Neuroscience doi:10.1523/JNEUROSCI.3278-10.2011
Drosophila Acyl-CoA Synthetase Long-Chain Family Member 4 Regulates Axonal Transport of Synaptic Vesicles and Is Required for Synaptic Development and Transmission
Zhihua Liu, Yan Huang, Yi Zhang, Di Chen, and Yong Q. Zhang
Acyl-CoA synthetase long-chain family member 4 (ACSL4) converts long-chain fatty acids to acyl-CoAs that are indispensable for lipid metabolism and cell signaling. Mutations in ACSL4 cause nonsyndromic X-linked mental retardation. We previously demonstrated that Drosophila dAcsl is functionally homologous to human ACSL4, and is required for axonal targeting in the brain. Here, we report that Drosophila dAcsl mutants exhibited distally biased axonal aggregates that were immunopositive for the synaptic-vesicle proteins synaptotagmin (Syt) and cysteine-string protein, the late endosome/lysosome marker lysosome-associated membrane protein 1, the autophagosomal marker Atg8, and the multivesicular body marker Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate). In contrast, the axonal distribution of mitochondria and the cell adhesion molecule Fas II (fasciclin II) was normal. Electron microscopy revealed accumulation of prelysomes and multivesicle bodies. These aggregates appear as retrograde instead of anterograde cargos. Live imaging analysis revealed that dAcsl mutations increased the velocity of anterograde transport but reduced the flux, velocity, and processivity of retrograde transport of Syt-enhanced green fluorescent protein-labeled vesicles. Immunohistochemical and electrophysiological analyses showed significantly reduced growth and stability of neuromuscular synapses, and impaired glutamatergic neurotransmission in dAcsl mutants. The axonal aggregates and synaptic defects in dAcsl mutants were fully rescued by neuronal expression of human ACSL4, supporting a functional conservation of ACSL4 across species in the nervous system. Together, our findings demonstrate that dAcsl regulates axonal transport of synaptic vesicles and is required for synaptic development and function. Defects in axonal transport and synaptic function may account, at least in part, for the pathogenesis of ACSL4-related mental retardation.
