Dopaminergic neurons of the substantia nigra exist in a persistent state of vulnerability resulting from high baseline oxidative stress, high‐energy demand, and broad unmyelinated axonal arborisations. Impairments in the storage of dopamine compound this stress because of cytosolic reactions that transform the vital neurotransmitter into an endogenous neurotoxicant, and this toxicity is thought to contribute to the dopamine neuron degeneration that occurs Parkinson's disease. We have previously identified synaptic vesicle glycoprotein 2C (SV2C) as a modifier of vesicular dopamine function, demonstrating that genetic ablation of SV2C in mice results in decreased dopamine content and evoked dopamine release in the striatum. Here, we adapted a previously published in vitro assay utilising false fluorescent neurotransmitter 206 (FFN206) to visualise how SV2C regulates vesicular dopamine dynamics and determined that SV2C promotes the uptake and retention of FFN206 within vesicles. In addition, we present data indicating that SV2C enhances the retention of dopamine in the vesicular compartment with radiolabelled dopamine in vesicles isolated from immortalised cells and from mouse brain. Further, we demonstrate that SV2C enhances the ability of vesicles to store the neurotoxicant 1‐methyl‐4‐phenylpyridinium (MPP+) and that genetic ablation of SV2C results in enhanced 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐induced vulnerability in mice. Together, these findings suggest that SV2C functions to enhance vesicular storage of dopamine and neurotoxicants and helps maintain the integrity of dopaminergic neurons.

中文翻译：

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突触小泡糖蛋白 2C 增强多巴胺的囊泡储存并对抗多巴胺能毒性

由于高基线氧化应激、高能量需求和广泛的无髓鞘轴突树枝化，黑质的多巴胺能神经元处于持续的脆弱状态。多巴胺储存受损会加剧这种压力，因为胞质反应会将重要的神经递质转化为内源性神经毒剂，而这种毒性被认为会导致帕金森病发生的多巴胺神经元变性。我们之前已经鉴定出突触小泡糖蛋白 2C (SV2C) 作为囊泡多巴胺功能的修饰剂，证明小鼠中 SV2C 的基因消除会导致多巴胺含量减少并引起纹状体中的多巴胺释放。在这里，我们采用了先前发表的体外测定，利用假荧光神经递质 206 (FFN206) 来可视化 SV2C 如何调节囊泡多巴胺动力学，并确定 SV2C 促进囊泡内 FFN206 的摄取和保留。此外，我们提供的数据表明，SV2C 增强了多巴胺在囊泡区室中的保留，而放射性标记的多巴胺在从永生化细胞和小鼠大脑中分离的囊泡中。此外，我们证明 SV2C 增强了囊泡储存神经毒剂 1-甲基-4-苯基吡啶鎓 (MPP+）并且 SV2C 的基因消除会导致 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的小鼠脆弱性增强。总之，这些发现表明 SV2C 的功能是增强多巴胺和神经毒物的囊泡储存，并有助于维持多巴胺能神经元的完整性。