Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis
Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson's disease pathogenesis
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DOI：
10.1038/s41467-019-08858-y
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发表时间：
2019-03-07
影响因子：
16.6
通讯作者：
Vila, Miquel
中科院分区：
文献类型：
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作者：
Carballo-Carbajal, Iria;Laguna, Ariadna;Vila, Miquel
在帕金森病（PD）中，含有神经黑色素的神经元，特别是黑质多巴胺能神经元选择性变性。在人类中，神经黑色素随着年龄的增长而积累，后者是帕金森病的主要危险因素。神经黑色素在帕金森病发病机制中的作用尚不清楚，因为与人类不同，普通实验动物缺乏神经黑色素。外周黑色素的合成是由酪氨酸酶介导的，酪氨酸酶在大脑中含量也很低。在这里，我们报告了大鼠黑质中人酪氨酸酶的过度表达导致黑质多巴胺能神经元中人样神经黑色素的年龄依赖性产生，达到老年人的水平。在这些动物中，细胞内神经黑色素积累超过特定阈值与年龄依赖性PD表型相关，包括运动障碍、路易体样形成和黑质纹状体神经变性。在酪氨酸酶过表达的动物中，增强溶酶体蛋白平衡可减少细胞内神经黑色素并防止神经退行性变。我们的研究结果表明，细胞内神经黑色素水平可能为PD的发生设定了阈值。
In Parkinson's disease (PD) there is a selective degeneration of neuromelanin-containing neurons, especially substantia nigra dopaminergic neurons. In humans, neuromelanin accumulates with age, the latter being the main risk factor for PD. The contribution of neuromelanin to PD pathogenesis remains unknown because, unlike humans, common laboratory animals lack neuromelanin. Synthesis of peripheral melanins is mediated by tyrosinase, an enzyme also present at low levels in the brain. Here we report that overexpression of human tyrosinase in rat substantia nigra results in age-dependent production of human-like neuromelanin within nigral dopaminergic neurons, up to levels reached in elderly humans. In these animals, intracellular neuromelanin accumulation above a specific threshold is associated to an age-dependent PD phenotype, including hypokinesia, Lewy body-like formation and nigrostriatal neurodegeneration. Enhancing lysosomal proteostasis reduces intracellular neuromelanin and prevents neurodegeneration in tyrosinase-overexpressing animals. Our results suggest that intracellular neuromelanin levels may set the threshold for the initiation of PD.