Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles
Neuromelanin biosynthesis is driven by excess cytosolic catecholamines not accumulated by synaptic vesicles
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DOI：
10.1073/pnas.97.22.11869
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发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Zecca, L
中科院分区：
文献类型：
--
作者：
Sulzer, D;Bogulavsky, J;Zecca, L
黑色素，头发，皮肤，眼睛和羽毛中的色素，保护外部组织免受紫外线的伤害。相比之下，神经黑色素（NM）被发现在脑深部区域，特别是在帕金森病退化的位点。虽然这种分布表明NM在帕金森病神经退行性变中的作用，但由于缺乏实验系统，NM的生物合成和功能无法表征。我们通过暴露于L-二羟基苯丙氨酸诱导大鼠黑质和PC 12细胞培养物中的NM，L-二羟基苯丙氨酸在胞质中迅速转化为多巴胺（DA）。这种色素与通过顺磁共振评估的人NM相同，并且定位于与人黑质NM颗粒相同的双膜自噬空泡中。通过腺病毒介导的突触囊泡儿茶酚胺转运体VMAT 2的过表达，通过增加神经递质的囊泡积累来减少胞质DA，从而废除NM合成。NM与三价铁形成稳定的复合物，铁螯合剂去铁胺抑制NM的合成，表明细胞质DA和二羟基苯丙氨酸通过铁介导的催化氧化为膜不渗透的醌和半醌。因此，NM合成是由于过量的胞质儿茶酚胺没有积累到突触囊泡中。永久积累过量的儿茶酚，醌，和儿茶酚加合物成膜不渗透物质被困在细胞器中，可能提供了一个抗氧化机制的儿茶酚胺神经元。然而，与分泌途径相关的细胞器中的NM可能干扰信号传导，因为它延迟了PC 12细胞中刺激的神经突生长。
Melanin, the pigment in hair, skin, eyes, and feathers, protects external tissue from damage by UV light. In contrast, neuromelanin (NM) is found in deep brain regions, specifically in loci that degenerate in Parkinson's disease. Although this distribution suggests a role for NM in Parkinson's disease neurodegeneration, the biosynthesis and function of NM have eluded characterization because of lack of an experimental system. We induced NM in rat substantia nigra and PC12 cell cultures by exposure to L-dihydroxy-phenylalanine, which is rapidly converted to dopamine (DA) in the cytosol. This pigment was identical to human NM as assessed by paramagnetic resonance and was localized in double membrane autophagic vacuoles identical to NM granules of human substantia nigra. NM synthesis was abolished by adenoviral-mediated overexpression of the synaptic vesicle catecholamine transporter VMAT2, which decreases cytosolic DA by increasing vesicular accumulation of neurotransmitter. The NM is in a stable complex with ferric iron, and NM synthesis was inhibited by the iron chelator desferrioxamine, indicating that cytosolic DA and dihydroxyphenylalanine are oxidized by iron-mediated catalysis to membrane-impermeant quinones and semiquinones. NM synthesis thus results from excess cytosolic catecholamines not accumulated into synaptic vesicles. The permanent accumulation of excess catechols, quinones, and catechol adducts into a membrane-impermeant substance trapped in organelles may provide an antioxidant mechanism for catecholamine neurons. However, NM in organelles associated with secretory pathways may interfere with signaling, as it delays stimulated neurite outgrowth in PC12 cells.