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）负责在神经传递过程中包装待释放的神经递质，并将毒物隔离于囊泡内以避免神经元损伤。在小鼠模型中，VMAT2水平低下会导致儿茶酚胺能细胞丢失，并出现类似帕金森病的行为表型；而VMAT2高表达则可增强多巴胺释放，同时抵御多巴胺能毒物的侵害。然而，此前由于不同遗传背景品系的差异，无法对不同VMAT2基因型的小鼠开展对比研究。
本研究通过将转基因小鼠回交至C57BL/6品系，证实了与野生型相比VMAT2水平低约95%的小鼠（VMAT2-LO）囊泡摄取能力显著降低，随衰老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）的毒性易感性显著加剧。
与之相反，VMAT2过表达小鼠（VMAT2-HI）在接受MPTP处理后，纹状体神经末梢的丢失情况得到有效保护。本研究还提供证据表明，VMAT2-HI小鼠增强的囊泡填充能力可改变新合成多巴胺的代谢处置过程，这一点可通过细胞外多巴胺清除的间接检测指标变化得到印证。
上述结果证实了VMAT2在保护脆弱的黑质纹状体多巴胺能神经元中的关键作用，同时也可为帕金森病左旋多巴（L-DOPA）治疗的不良反应提供新的研究见解。