Journal article

L-3,4-dihydroxyphenylalanine (L-DOPA) modulates brain iron, dopaminergic neurodegeneration and motor dysfunction in iron overload and mutant alpha-synuclein mouse models of Parkinson's disease

Jessica L Billings, Sarah L Gordon, Tristan Rawling, Philip A Doble, Ashley I Bush, Paul A Adlard, David I Finkelstein, Dominic J Hare



Treatment with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA) provides symptomatic relief arising from DA denervation in Parkinson's disease. Mounting evidence that DA autooxidation to neurotoxic quinones is involved in Parkinson's disease pathogenesis has raised concern about potentiation of oxidative stress by l-DOPA. The rate of DA quinone formation increases in the presence of excess redox-active iron (Fe), which is a pathological hallmark of Parkinson's disease. Conversely, l-DOPA has pH-dependent Fe-chelating properties, and may act to 'redox silence' Fe and partially allay DA autoxidation. We examined the effects of l-DOPA in three murine models of parkinsonian neur..

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Awarded by Australian Research Council

Awarded by National Health and Medical Research Council

Funding Acknowledgements

We thank Professor Virginia Lee for providing the original hA53T mouse line from which animals in this report were descendants. We also thank Ms Milawaty Nurjono for assistance with animal culling. The Florey Institute of Neuroscience and Mental Health acknowledge the strong support from the Victorian Government and in particular the funding from the Operational Infrastructure Support Grant. P.A.D and D.J.H. are supported by funds from the Australian Research Council Linkage Project scheme in partnership with Agilent Technologies and ESI Ltd (LP120200081). P.A.A. received a Future Fellowship from the Australian Research Council (FT120100030). The National Health and Medical Research Council supported this work with funds to S.L.G. (Career Development Fellowship 1085483), A.I.B. (Program Grant 1132604; Research Fellowship 1103703), P.A.A. (Project Grant 1025774), D.I.F. (Project Grants 1061761, 1044542, 1043992 and 509286) and D.J.H. (Career Development Fellowship in partnership with Agilent Technologies 1122981). D.I.F. also receives support from the Michael J. Fox Foundation for Parkinson's Research. P.A.A. and D.I.F. are paid consultants to and shareholders in Prana Biotechnology Ltd. A.I.B. is a shareholder in Prana Biotechnology Ltd., Mesoblast Pty Ltd., Cogstate Pty Ltd., NextVet Ltd., Collaborative Medicinal Development Pty Ltd., and a payed consultant for Collaborative Medicinal Development Pty Ltd. P.A.D. and D.J.H. receive material and research support from Agilent Technologies and ESI Ltd.