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

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 alpha-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 alpha-synuclein into dihydroxyphenylalanine (DOPA; Y136DOPA) through mass spectrometric analysis. Y136DOPA modification was clearly detected by a specific antibody in the dopaminergic neurons of alpha-synuclein-overexpressing mice as well as human alpha-synucleinopathies. Furthermore, dopanized alpha-synuclein tended to form oligomers rather than large fibril aggregates and significantly enhanced neurotoxicity. Our findings suggest that the dopanization of alpha-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 alpha-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.