Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.
Age-associated insolubility of parkin in human midbrain is linked to redox balance and sequestration of reactive dopamine metabolites.
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Parkin在人中脑中与年龄相关的不溶性与反应性多巴胺代谢产物的氧化还原平衡和隔离有关。
DOI：
10.1007/s00401-021-02285-4
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发表时间：
2021-05
影响因子：
12.7
通讯作者：
Schlossmacher MG
中科院分区：
文献类型：
--
作者：
Tokarew JM;El-Kodsi DN;Lengacher NA;Fehr TK;Nguyen AP;Shutinoski B;O'Nuallain B;Jin M;Khan JM;Ng ACH;Li J;Jiang Q;Zhang M;Wang L;Sengupta R;Barber KR;Tran A;Im DS;Callaghan S;Park DS;Zandee S;Dong X;Scherzer CR;Prat A;Tsai EC;Takanashi M;Hattori N;Chan JA;Zecca L;West AB;Holmgren A;Puente L;Shaw GS;Toth G;Woulfe JM;Taylor P;Tomlinson JJ;Schlossmacher MG
Parkin 保护成人大脑免受帕金森病侵害的机制仍不完全清楚。我们假设 Parkin 半胱氨酸参与氧化还原反应，并且这些反应反映在其翻译后修饰中。我们发现，在死后的人类大脑中，包括黑质中，parkin 在 40 岁后基本上无法溶解；这种转变与其氧化有关，例如残基 Cys95 和 Cys253 处的氧化。在小鼠中，氧化应激会诱导 Parkin 半胱氨酸发生翻译后修饰，从而降低其在体内的溶解度。类似地，重组parkin被过氧化氢（H2O2）氧化促进其不溶性和聚集体形成，并且作为交换导致H2O2的还原。这种基于硫醇的氧化还原活性会被 Parkin 点突变体（例如 p.C431F 和 p.G328E）减弱。在 prkn 缺失的小鼠中，H2O2 水平在氧化应激条件下会升高，例如由于 1-甲基-4-苯基-1,2,3,6-四氢吡啶毒素暴露而急性升高，或由于第二次基因打击而慢性升高；在帕金缺陷的人脑中，H2O2 水平也显着增加。 在多巴胺毒性研究中，野生型 Parkin（而非疾病相关突变体）可以部分通过降低 H2O2 来保护人类多巴胺能细胞。 Parkin 还通过加合物形成来中和反应性亲电子多巴胺代谢物，加合物首先发生在灵长类动物特异性残基 Cys95 处。此外，野生型而非 p.C95A 突变型 Parkin 会在体外增强黑色素形成。 通过使用表位作图的单克隆抗体探测对照个体的成人、人类中脑切片，我们发现了特异性且强大的 Parkin 反应性，该反应性与神经黑色素色素共定位，通常位于 LAMP-3/CD63+ 溶酶体中。我们得出的结论是，parkin 半胱氨酸的氧化修饰与保护性结果相关，包括减少 H2O2、反应性多巴胺代谢物的结合、不溶性聚集体中自由基的螯合以及黑色素形成的增加。这些互补氧化还原效应的丧失可能会增加突变 PRKN 等位基因携带者的多巴胺产生细胞衰老过程中的氧化应激，从而增加帕金森氏症相关神经变性的风险。在线版本包含可在 10.1007/s00401-021-02285-4 获取的补充材料。
The mechanisms by which parkin protects the adult human brain from Parkinson disease remain incompletely understood. We hypothesized that parkin cysteines participate in redox reactions and that these are reflected in its posttranslational modifications. We found that in post mortem human brain, including in the Substantia nigra, parkin is largely insoluble after age 40 years; this transition is linked to its oxidation, such as at residues Cys95 and Cys253. In mice, oxidative stress induces posttranslational modifications of parkin cysteines that lower its solubility in vivo. Similarly, oxidation of recombinant parkin by hydrogen peroxide (H2O2) promotes its insolubility and aggregate formation, and in exchange leads to the reduction of H2O2. This thiol-based redox activity is diminished by parkin point mutants, e.g., p.C431F and p.G328E. In prkn-null mice, H2O2 levels are increased under oxidative stress conditions, such as acutely by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxin exposure or chronically due to a second, genetic hit; H2O2 levels are also significantly increased in parkin-deficient human brain. In dopamine toxicity studies, wild-type parkin, but not disease-linked mutants, protects human dopaminergic cells, in part through lowering H2O2. Parkin also neutralizes reactive, electrophilic dopamine metabolites via adduct formation, which occurs foremost at the primate-specific residue Cys95. Further, wild-type but not p.C95A-mutant parkin augments melanin formation in vitro. By probing sections of adult, human midbrain from control individuals with epitope-mapped, monoclonal antibodies, we found specific and robust parkin reactivity that co-localizes with neuromelanin pigment, frequently within LAMP-3/CD63+ lysosomes. We conclude that oxidative modifications of parkin cysteines are associated with protective outcomes, which include the reduction of H2O2, conjugation of reactive dopamine metabolites, sequestration of radicals within insoluble aggregates, and increased melanin formation. The loss of these complementary redox effects may augment oxidative stress during ageing in dopamine-producing cells of mutant PRKN allele carriers, thereby enhancing the risk of Parkinson’s-linked neurodegeneration. The online version contains supplementary material available at 10.1007/s00401-021-02285-4.
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帕金氏病：临床病理学实体？
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DOI：
10.1126/science.aad2459
发表时间：
2015-12-04
期刊：
Science (New York, N.Y.)
影响因子：
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