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

Mingyue Jin, Sakiko Matsumoto, Takashi Ayaki, Hodaka Yamakado, Tomoyuki Taguchi, Natsuko Togawa, Ayumu Konno, Hirokazu Hirai, Hiroshi Nakajima, Shoji Komai, Ryuichi Ishida, Syuhei Chiba, Ryosuke Takahashi, Toshifumi Takao and Shinji Hirotsune ()
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Mingyue Jin: Osaka Metropolitan University Graduate School of Medicine
Sakiko Matsumoto: Osaka Metropolitan University Graduate School of Medicine
Takashi Ayaki: Kyoto University Graduate School of Medicine
Hodaka Yamakado: Kyoto University Graduate School of Medicine
Tomoyuki Taguchi: Kyoto University Graduate School of Medicine
Natsuko Togawa: Kyoto University Graduate School of Medicine
Ayumu Konno: Gunma University Graduate School of Medicine
Hirokazu Hirai: Gunma University Graduate School of Medicine
Hiroshi Nakajima: Osaka Metropolitan University Graduate School of Science
Shoji Komai: Nara Institute of Science Technology
Ryuichi Ishida: Osaka Metropolitan University Graduate School of Medicine
Syuhei Chiba: Osaka Metropolitan University Graduate School of Medicine
Ryosuke Takahashi: Kyoto University Graduate School of Medicine
Toshifumi Takao: Osaka University Institute for Protein Research
Shinji Hirotsune: Osaka Metropolitan University Graduate School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-34555-4

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