Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
Department of Environmental Health, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.
Toxicol Sci. 2021 Apr 12;180(2):313-324. doi: 10.1093/toxsci/kfab011.
The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode Caenorhabditis elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this article was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that high-resolution mass spectrometry-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease.
单胺类物质的正确储存和释放有助于神经元的广泛活动。在这里，我们研究了在秀丽隐杆线虫中改变囊泡单胺转运的影响。cat-1 基因负责编码线虫中的囊泡单胺转运体（VMAT），与哺乳动物的囊泡单胺转运体 2（VMAT2）类似。我们实验室之前已经表明，降低 VMAT2 活性会使小鼠中的儿茶酚胺神经元变得脆弱。本文的目的是确定这种功能是否保守，并确定在秀丽隐杆线虫中降低 VMAT 活性的影响。在这里，我们表明 cat-1/VMAT 的缺失会增加多巴胺神经元对神经毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPP+）的敏感性，如多巴胺神经元退化增强所测量的。减少 cat-1/VMAT 也会导致多巴胺介导的行为发生变化。基于高分辨率质谱的全生物体代谢组学研究揭示了氨基酸代谢的变化，包括 cat-1/VMAT 突变体中的酪氨酸代谢。MPP+处理会破坏色氨酸代谢。这两种情况都改变了甘油磷脂代谢，表明存在神经元功能障碍的趋同途径。我们的研究结果表明单胺功能在秀丽隐杆线虫中具有进化上的保守性，并进一步表明基于高分辨率质谱的代谢组学可以用于该模型来研究环境和遗传因素对复杂人类疾病的影响。
