DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers.

Autor: Jin, Mingyue, Matsumoto, Sakiko, Ayaki, Takashi, Yamakado, Hodaka, Taguchi, Tomoyuki, Togawa, Natsuko, Konno, Ayumu, Hirai, Hirokazu, Nakajima, Hiroshi, Komai, Shoji, Ishida, Ryuichi, Chiba, Syuhei, Takahashi, Ryosuke, Takao, Toshifumi, Hirotsune, Shinji
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Zdroj: Nature Communications; 11/12/2022, Vol. 13 Issue 1, p1-11, 11p
Abstrakt: 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. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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