酯酰辅酶A合成酶长链家族成员4（ACSL4）是脂代谢中一个重要的酶，它催化长链脂肪酸和辅酶A反应生成酯酰辅酶A。这个步骤使长链脂肪酸活化而进入脂类合成和能量代谢。因此，ACSL4对于许多代谢途径和信号途径都是必须的。这个基因的突变可导致智力发育迟滞(mental retardation)，但其发病机制还远不清楚。
中科院遗传与发育生物学研究所王朝晖研究组最先建立了该疾病的果蝇模型（Zhang et al., Hum Mol Genet, 2009）。在最新研究中，该所张永清研究组利用这个模型，进一步在果蝇的神经肌肉系统中分析了该基因的功能。他们发现，dAcsl突变体的运动神经元轴突中存在大量突触囊泡蛋白的聚集，而线粒体和细胞粘连分子Fasciclin II在轴突中的分布却没有变化。结合免疫染色和电镜，他们确定这些聚集物主要是晚期胞内体（late endosome）/溶酶体（lysosome）以及多囊泡结构（Multivesicular bodies）等。而这些结构被认为是反向轴突运输的货物，提示dAcsl突变体中反向轴突运输可能受损。
利用活体成像的方法，研究人员进一步直接观察到突变体中用GFP标记的囊泡的反向运输速度、流量以及运动的连续性受损，而正向运输的速度稍有加快。伴随反向运输缺陷，他们发现突变体轴突较长的运动神经元突触萎缩并在发育过程中回缩，且这些突触的电活动传导也减弱。这些结果说明，dAcsl参与调控轴突的囊泡运输和突触发育。尤为重要的是，果蝇dAcsl突变体在神经系统的表型都可通过表达人类ACSL4所挽救，说明人类ACSL4和果蝇dAcsl的功能在进化上高度保守。
这些发现对ACSL4突变如何导致智力发育迟滞的分子机制提供了全新的见解，也为将来治疗或缓解病人的脑功能障碍提供了理论基础。该研究发表于2011年2月The Journal of Neuroscience杂志。张永清实验室研究生刘志华为该论文第一作者。
该项目得到国家自然科学基金和科技部的资助。（生物谷Bioon.com）
生物谷推荐原文出处：
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.
