Data from: Vesicular monoamine transporter 2 (VMAT2) level regulates MPTP vulnerability and clearance of excess dopamine in mouse striatal terminals

The vesicular monoamine transporter 2 (VMAT2) packages neurotransmitters for release during neurotransmission and sequesters toxicants into vesicles to prevent neuronal damage. In mice, low VMAT2 levels causes catecholaminergic cell loss and behaviors resembling Parkinson’s disease, while high levels of VMAT2 increase dopamine release and protect against dopaminergic toxicants. However, comparisons across these VMAT2 mouse genotypes were impossible due to the differing genetic background strains of the animals. Following back-crossing to a C57BL/6 line, we confirmed that mice with approximately 95% lower VMAT2 levels compared with wild-type (VMAT2-LO) display significantly reduced vesicular uptake, progressive dopaminergic terminal loss with aging, and exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Conversely, VMAT2-overexpressing mice (VMAT2-HI) are protected from the loss of striatal terminals following MPTP treatment. We also provide evidence that enhanced vesicular filling in the VMAT2-HI mice modifies the handling of newly synthesized dopamine, indicated by changes in indirect measures of extracellular dopamine clearance. These results confirm the role of VMAT2 in the protection of vulnerable nigrostriatal dopamine neurons and may also provide new insight into the side effects of L-DOPA treatments in Parkinson’s disease.

囊泡单胺转运体2（vesicular monoamine transporter 2，VMAT2）可在神经传递过程中包装神经递质以供释放，并将有毒物质隔离至囊泡内以避免神经元受损。在小鼠模型中，囊泡单胺转运体2水平较低会导致儿茶酚胺能神经元丢失，并出现类似帕金森病（Parkinson’s disease）的行为表型；而囊泡单胺转运体2水平升高则可增加多巴胺释放，并对抗多巴胺能神经毒物的损伤。然而，由于这些小鼠的遗传背景品系存在差异，此前无法对不同VMAT2基因型的小鼠开展比较研究。本研究通过将转基因小鼠回交至C57BL/6品系后证实，与野生型小鼠（wild-type）相比，囊泡单胺转运体2水平仅为野生型95%左右的小鼠（VMAT2低表达小鼠，VMAT2-LO），其囊泡摄取能力显著降低，随衰老会出现进行性多巴胺能神经末梢丢失，且对1-甲基-4-苯基-1,2,3,6-四氢吡啶（1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine，MPTP）的毒性易感性加剧。与之相反，过表达囊泡单胺转运体2的小鼠（VMAT2高表达小鼠，VMAT2-HI）在接受MPTP处理后，其纹状体神经末梢的丢失现象得到缓解。本研究还证实，VMAT2-HI小鼠的囊泡填充能力增强，可改变新合成多巴胺的代谢处理过程，这一现象可通过细胞外多巴胺清除的间接检测指标变化得到体现。上述研究结果证实了囊泡单胺转运体2在保护脆弱的黑质纹状体多巴胺能神经元中的作用，同时也可为帕金森病患者的左旋多巴（L-DOPA）治疗副作用研究提供新的视角。