Abstract

Parkinson's disease (PD) is defined by the loss of dopaminergic neurons in the substantia nigra and the formation of Lewy body inclusions containing aggregated α-synuclein. Efforts to explain dopamine neuron vulnerability are hindered by the lack of dopaminergic cell death in α-synuclein transgenic mice. To address this, we manipulated both dopamine levels and α-synuclein expression. Nigrally targeted expression of mutant tyrosine hydroxylase with enhanced catalytic activity increased dopamine levels without damaging neurons in non-transgenic mice. In contrast, raising dopamine levels in mice expressing human A53T mutant α-synuclein induced progressive nigrostriatal degeneration and reduced locomotion. Dopamine elevation in A53T mice increased levels of potentially toxic α-synuclein oligomers, resulting in conformationally and functionally modified species. Moreover, in genetically tractable Caenorhabditis elegans models, expression of α-synuclein mutated at the site of interaction with dopamine prevented dopamine-induced toxicity. These data suggest that a unique mechanism links two cardinal features of PD: dopaminergic cell death and α-synuclein aggregation.

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Acknowledgements

We thank T. Clarke and T. Pierson from the Wolfe lab for technical assistance with animals and for helpful advice on vector production. We thank H. Bennett from the Kalb lab for initial work on the dopamine neuron degeneration assay in C. elegans and input on worm breeding. We thank L. Spruce, H. Fazelinia and S. Seeholzer from the Children's Hospital of Philadelphia Proteomic Core facility for mass spectrometry. We thank V. Lee (University of Pennsylvania) and G. Miller (Emory University) for generously providing α-synuclein and VMAT2 antibodies, respectively, and S. Przedborski (Columbia University) for the use of stereology equipment and helpful feedback on the manuscript. Finally, we thank R. Lightfoot and members of the Ischiropoulos lab for productive discussions and technical support. This work was supported by grants from the US National Institutes of Health: AG013966 (H.I.), NS038690 (J.H.W.) and NS087077 and NS052325 (R.G.K.). D.E.M. was supported by the US National Institutes of Health Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship NS087779. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Affiliations

  1. Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Danielle E Mor
    • , Shachee Doshi
    • , Preetika Gupta
    • , Robert G Kalb
    • , John H Wolfe
    •  & Harry Ischiropoulos
  2. AC Immune SA, École Polytechnique fédérale de Lausanne Innovation Park, Lausanne, Switzerland.

    • Elpida Tsika
  3. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Joseph R Mazzulli
  4. Children's Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA.

    • Neal S Gould
    • , Robert G Kalb
    • , John H Wolfe
    •  & Harry Ischiropoulos
  5. Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA.

    • Hanna Kim
    • , Kim A Caldwell
    •  & Guy A Caldwell
  6. Pharmacology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Malcolm J Daniels
    •  & Harry Ischiropoulos
  7. State University of New York Downstate College of Medicine, Brooklyn, New York, USA.

    • Jennifer L Grossman
  8. College of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Victor X Tan
  9. W.F. Goodman Center for Comparative Medical Genetics, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • John H Wolfe

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Contributions

D.E.M., E.T., J.R.M., R.G.K. and H.I. conceived and designed the experiments. D.E.M., E.T., H.K., N.S.G., M.J.D., S.D., P.G., J.L.G. and V.X.T. performed the experiments and analyzed the data. D.E.M. wrote the paper, with important contributions from J.R.M., E.T., J.H.W., R.G.K., K.A.C., G.A.C. and H.I.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Harry Ischiropoulos.

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https://doi.org/10.1038/nn.4641

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