CID-CSIC, Jordi Girona 18, 08034, Barcelona, Spain.
IDAEA-CSIC, Jordi Girona 18, 08034, Barcelona, Spain.
Sci Rep. 2017 Oct 24;7(1):13952. doi: 10.1038/s41598-017-14460-3.
Acrylamide (ACR), a type-2 alkene, may lead to a synaptopathy characterized by ataxia, skeletal muscles weakness and numbness of the extremities in exposed human and laboratory animals. Currently, only the mildly affected patients undergo complete recovery, and identification of new molecules with therapeutic bioactivity against ACR acute neurotoxicity is urgently needed. Here, we have generated a zebrafish model for ACR neurotoxicity by exposing 5 days post-fertilization zebrafish larvae to 1 mM ACR for 3 days. Our results show that zebrafish mimics most of the pathophysiological processes described in humans and mammalian models. Motor function was altered, and specific effects were found on the presynaptic nerve terminals at the neuromuscular junction level, but not on the axonal tracts or myelin sheath integrity. Transcriptional markers of proteins involved in synaptic vesicle cycle were selectively altered, and the proteomic analysis showed that ACR-adducts were formed on cysteine residues of some synaptic proteins. Finally, analysis of neurotransmitters profile showed a significant effect on cholinergic and dopaminergic systems. These data support the suitability of the developed zebrafish model for screening of molecules with therapeutic value against this toxic neuropathy.
丙烯酰胺（ACR），一种 2 型烯烃，可能导致以共济失调为特征的突触病，骨骼肌肉无力和四肢麻木在暴露于人类和实验室动物中。目前，只有轻度受影响的患者才能完全康复，因此迫切需要鉴定具有治疗丙烯酰胺急性神经毒性的生物活性的新分子。在这里，我们通过将 5 天大的斑马鱼幼虫暴露于 1mM ACR 3 天来建立 ACR 神经毒性的斑马鱼模型。我们的结果表明，斑马鱼模拟了大多数在人类和哺乳动物模型中描述的病理生理过程。运动功能发生改变，并且在神经肌肉接头水平的突触前神经末梢上发现了特定的影响，但不在轴突束或髓鞘完整性上。参与突触小泡循环的蛋白质的转录标记物被选择性地改变，蛋白质组学分析表明 ACR 加合物形成在一些突触蛋白的半胱氨酸残基上。最后，对神经递质谱的分析显示对胆碱能和多巴胺能系统有显著影响。这些数据支持开发的斑马鱼模型适合筛选对这种毒性神经病具有治疗价值的分子。
