title: Tyrosinase exacerbates dopamine toxicity but is not genetically associated with Parkinson's disease.
abstract: Tyrosinase is a key enzyme in the synthesis of melanin in skin and hair and has also been proposed to contribute to the formation of neuromelanin (NM). The presence of NM, which is biochemically similar to melanin in peripheral tissues, identifies groups of neurons susceptible in Parkinson's disease (PD). Whether tyrosinase is beneficial or detrimental to neurons is unclear; whilst the enzyme activity of tyrosinase generates dopamine-quinones and other oxidizing compounds, NM may form a sink for such radical species. In the present study, we demonstrated that tyrosinase is expressed at low levels in the human brain. We found that mRNA, protein and enzyme activity are all present but at barely detectable levels. In cell culture systems, expression of tyrosinase increases neuronal susceptibility to oxidizing conditions, including dopamine itself. We related these in vitro observations to the human disease by assessing whether there was any genetic association between the gene encoding tyrosinase and idiopathic PD. We found neither genotypic or haplotypic association with three polymorphic markers of the gene. This argues against a strong genetic association between tyrosinase and PD, although the observed contribution to cellular toxicity suggests that a biochemical association is likely.
authors.affiliation: Department of Biology, University of Padova, Padova, Italy. elisa@cribi.unipd.it
authors.forename: Elisa
authors.initials: E
authors.lastname: Greggio
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bergantino
authors.forename: Donald
authors.initials: D
authors.lastname: Carter
authors.forename: Rili
authors.initials: R
authors.lastname: Ahmad
authors.forename: Gertrude-Emilia
authors.initials: GE
authors.lastname: Costin
authors.forename: Vincent J
authors.initials: VJ
authors.lastname: Hearing
authors.forename: Jordi
authors.initials: J
authors.lastname: Clarimon
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Johanna
authors.initials: J
authors.lastname: Eerola
authors.forename: Olli
authors.initials: O
authors.lastname: Hellström
authors.forename: Pentti J
authors.initials: PJ
authors.lastname: Tienari
authors.forename: David W
authors.initials: DW
authors.lastname: Miller
authors.forename: Alexandra
authors.initials: A
authors.lastname: Beilina
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002478:Cells, Cultured; D003001:Cloning, Molecular / Q000379:methods; D004298:Dopamine / Q000633:toxicity*; D004347:Drug Interactions; D005260:Female; D005455:Fluorescent Antibody Technique / Q000379:methods; D005787:Gene Frequency / Q000502:physiology; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D051379:Mice; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000494:pharmacology / Q000502:physiology*; D009447:Neuroblastoma; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011180:Postmortem Changes; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013778:Tetrazolium Salts; D013844:Thiazoles; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D014162:Transfection / Q000379:methods
chemical_list: D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; D014442:Monophenol Monooxygenase; C022616:thiazolyl blue; D004298:Dopamine