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Dopamine covalently modifies and functionally inactivates parkin

Nature Medicine volume 11, pages 1214–1221 (2005)Cite this article

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Abstract

Inherited mutations in PARK2, the gene encoding parkin, cause selective degeneration of catecholaminergic neurons in the substantia nigra and locus coeruleus of the brainstem, resulting in early-onset parkinsonism. But the role of parkin in common, sporadic forms of Parkinson disease remains unclear. Here we report that the neurotransmitter dopamine covalently modifies parkin in living dopaminergic cells, a process that increases parkin insolubility and inactivates its E3 ubiquitin ligase function. In the brains of individuals with sporadic Parkinson disease, we observed decreases in parkin solubility consistent with its functional inactivation. Using a new biochemical method, we detected catechol-modified parkin in the substantia nigra but not other regions of normal human brain. These findings show a vulnerability of parkin to modification by dopamine, the principal transmitter lost in Parkinson disease, suggesting a mechanism for the progressive loss of parkin function in dopaminergic neurons during aging and sporadic Parkinson disease.

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Figure 1: Dopamine-induced insolubility and oligomerization of parkin.
Figure 2: Dopamine induces a selective loss of endogenous parkin in two neural cell lines.
Figure 3: Covalent attack of parkin by dopamine quinone and inactivation of parkin's E3 ligase activity.
Figure 4: Selective increase in insoluble parkin in the caudate nucleus of idiopathic Parkinson disease brains.
Figure 5: Biochemical isolation of catechol-modified proteins from human brain.

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Notes

  1. NOTE: In the version of this article initially published online, the Supplementary Methods contained two extraneous phrases. The error has been corrected for the HTML version of the article.

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Acknowledgements

We thank J. Chan (Brigham and Women's Hospital) and M. Frosch (Massachusetts ADRC) for providing human brain tissue, and the patients and their families for tissue donation. We thank E. Pothos and T.G. Hastings for technical expertise and assistance. We also thank S. Appel for the MES dopaminergic neuronal cell line, J. Trojanowski for the PRK8 antibody and N. Hattori and Y. Mizuno for human autosomal recessive Parkinson disease specimens. We are grateful to our many colleagues for providing expression vectors and other reagents and to D. Walsh, V. Cullen, S. Baulac, J. Palacino and R.R. Ratan for helpful discussions and reagents. This work was supported by a grant from the American Parkinson Disease Association (to M.J.L.), Udall Center of Excellence grant NS38375 (to D.J.S., M.G.S.) and a grant from the Harvard Center for Neurodegeneration and Repair (to M.G.S.) and an EMBO Long-Term Fellowship (to A.W.).

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  1. Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 7th Floor, Boston, 02115, Massachusetts, USA

    Matthew J LaVoie, Andreas Weihofen, Michael G Schlossmacher & Dennis J Selkoe

  2. Harvard Medical School, 77 Avenue Louis Pasteur, HIM 7th Floor, Boston, 02115, Massachusetts, USA

    Matthew J LaVoie, Beth L Ostaszewski, Andreas Weihofen, Michael G Schlossmacher & Dennis J Selkoe

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  1. Matthew J LaVoie
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Correspondence to Matthew J LaVoie.

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Supplementary information

Supplementary Fig. 1

Characterization of the dopaminergic MES cell line and antibodies used. (PDF 223 kb)

Supplementary Fig. 2

Further examination of dopamine-Parkin interactions and sex, post mortem interval, and age at death of human subjects used in Fig. 4. (PDF 290 kb)

Supplementary Methods (PDF 43 kb)

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LaVoie, M., Ostaszewski, B., Weihofen, A. et al. Dopamine covalently modifies and functionally inactivates parkin. Nat Med 11, 1214–1221 (2005). https://doi.org/10.1038/nm1314

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