DOPAnization of tyrosine in α-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.

Automated summary

Parkinson's disease is a progressive neurodegenerative disorder, and research suggests that tyrosine hydroxylase can facilitate the formation of oligomers of alpha-synuclein through dopamine modification, potentially impacting disease pathogenesis and degeneration of dopaminergic neurons.