Dopamine covalently modifies and functionally inactivates parkin.
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.
LaVoie
Matthew J
MJ
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, HIM 7th Floor, Boston, Massachusetts 02115, USA. mlavoie@rics.bwh.harvard.edu
Ostaszewski
Beth L
BL
Weihofen
Andreas
A
Schlossmacher
Michael G
MG
Selkoe
Dennis J
DJ
D000328:Adult; D000818:Animals; D015153:Blotting, Western; D001923:Brain Chemistry; D016466:CHO Cells; D002250:Carbon Radioisotopes / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D004298:Dopamine / Q000378:metabolism* / Q000633:toxicity*; D015259:Dopamine Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008125:Locus Coeruleus / Q000166:cytology / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology; D009154:Mutation; D009474:Neurons / Q000187:drug effects; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D011233:Precipitin Tests; D012995:Solubility; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
D002250:Carbon Radioisotopes; D015259:Dopamine Agents; D008694:Methamphetamine; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine