DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers.
DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers.
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DOI：
10.1038/s41467-022-34555-4
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发表时间：
2022-11-12
影响因子：
16.6
通讯作者：
Hirotsune S
中科院分区：
文献类型：
--
作者：
Jin M;Matsumoto S;Ayaki T;Yamakado H;Taguchi T;Togawa N;Konno A;Hirai H;Nakajima H;Komai S;Ishida R;Chiba S;Takahashi R;Takao T;Hirotsune S
帕金森病是一种进行性神经退行性疾病，其特征是黑质中表达酪氨酸羟化酶 (TH) 的多巴胺能神经元优先丧失。尽管α-突触核蛋白的异常积累和聚集与帕金森病的发病机制有关，但其潜在机制在很大程度上仍不清楚。在这里，我们通过质谱分析发现TH将α-突触核蛋白中的Tyr136转化为二羟基苯丙氨酸（DOPA；Y136DOPA）。 Y136DOPA 修饰可通过 α-突触核蛋白过表达小鼠以及人类 α-突触核蛋白病的多巴胺能神经元中的特异性抗体清楚地检测到。此外，掺杂的 α-突触核蛋白倾向于形成寡聚物而不是大的原纤维聚集体，并且显着增强神经毒性。我们的研究结果表明，TH 对 α-突触核蛋白的多潘化可能有助于寡聚体和/或种子形成，从而导致神经变性，并有可能揭示帕金森病的发病机制。在这项工作中，作者表明 α-突触核蛋白在 Tyr136 处被酪氨酸羟化酶翻译后掺杂，从而促进寡聚体的形成。这种修饰可能会影响帕金森病的发病机制和多巴胺能神经元的选择性变性。
Parkinson’s disease is a progressive neurodegenerative disorder characterized by the preferential loss of tyrosine hydroxylase (TH)-expressing dopaminergic neurons in the substantia nigra. Although the abnormal accumulation and aggregation of α-synuclein have been implicated in the pathogenesis of Parkinson’s disease, the underlying mechanisms remain largely elusive. Here, we found that TH converts Tyr136 in α-synuclein into dihydroxyphenylalanine (DOPA; Y136DOPA) through mass spectrometric analysis. Y136DOPA modification was clearly detected by a specific antibody in the dopaminergic neurons of α-synuclein-overexpressing mice as well as human α-synucleinopathies. Furthermore, dopanized α-synuclein tended to form oligomers rather than large fibril aggregates and significantly enhanced neurotoxicity. Our findings suggest that the dopanization of α-synuclein by TH may contribute to oligomer and/or seed formation causing neurodegeneration with the potential to shed light on the pathogenesis of Parkinson’s disease. In this work, the authors show that α-synuclein is posttranslationally dopanized at Tyr136 by tyrosine hydroxylase, which facilitates the formation of oligomers. This modification likely impacts pathogenesis and the selective degeneration of dopaminergic neurons in Parkinson’s disease.
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影响因子：
16.6
作者：
Cascella R;Chen SW;Bigi A;Camino JD;Xu CK;Dobson CM;Chiti F;Cremades N;Cecchi C
通讯作者：
Cecchi C
影响因子：
6.1
作者：
Dyson, H. Jane
通讯作者：
Dyson, H. Jane
影响因子：
12.7
作者：
Bengoa-Vergniory N;Roberts RF;Wade-Martins R;Alegre-Abarrategui J
通讯作者：
Alegre-Abarrategui J
影响因子：
168.9
作者：
Chartier-Harlin, MC;Kachergus, J;Destée, A
通讯作者：
Destée, A
影响因子：
16.2
作者：
Giasson, BI;Duda, JE;Lee, VMY
通讯作者：
Lee, VMY