The reaction of alpha-synuclein with tyrosinase: possible implications for Parkinson disease.
Oxidative stress appears to be directly involved in the pathogenesis of Parkinson disease. Several different pathways have been identified for the production of oxidative stress conditions in nigral dopaminergic neurons, including a pathological accumulation of cytosolic dopamine with the subsequent production of toxic reactive oxygen species or the formation of highly reactive quinone species. On these premises, tyrosinase, a key copper enzyme known for its role in the synthesis of melanin in skin and hair, has been proposed to take part in the oxidative chemistry related to Parkinson disease. A study is herein presented of the in vitro reactivity of tyrosinase with alpha-synuclein, aimed at defining the molecular basis of their synergistic toxic effect. The results presented here indicate that, in conformity with the stringent specificity of tyrosinase, the exposed tyrosine side-chains are the reactive centers of alpha-synuclein. The reactivity of alpha-synuclein depends on whether it is free or membrane bound, and the chemical modifications on the tyrosinase-treated alpha-synuclein strongly influence its aggregation properties. On the basis of our results, we propose a cytotoxic model which includes a possible new toxic role for alpha-synuclein exacerbated by its direct chemical modification by tyrosinase.
Tessari
Isabella
I
Department of Biology, University of Padova, Padova 35121, Italy.
Bisaglia
Marco
M
Valle
Francesco
F
Samorì
Bruno
B
Bergantino
Elisabetta
E
Mammi
Stefano
S
Bubacco
Luigi
L
D002942:Circular Dichroism; D003600:Cytosol / Q000378:metabolism; D004298:Dopamine / Q000737:chemistry; D006801:Humans; D008954:Models, Biological; D014442:Monophenol Monooxygenase / Q000737:chemistry* / Q000378:metabolism; D009154:Mutation; D010100:Oxygen / Q000737:chemistry; D010300:Parkinson Disease / Q000378:metabolism*; D011809:Quinones / Q000737:chemistry; D017382:Reactive Oxygen Species; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors; D014443:Tyrosine / Q000737:chemistry; D051844:alpha-Synuclein / Q000378:metabolism*
D011809:Quinones; D017382:Reactive Oxygen Species; D051844:alpha-Synuclein; D014443:Tyrosine; D014442:Monophenol Monooxygenase; D010100:Oxygen; D004298:Dopamine