title: Parkin degrades estrogen-related receptors to limit the expression of monoamine oxidases.
abstract: Parkin, whose mutations cause Parkinson disease (PD), controls oxidative stress by limiting the expression of monoamine oxidases (MAO)--mitochondrial enzymes responsible for the oxidative de-amination of dopamine. Here, we show that parkin performed this function by increasing the ubiquitination and degradation of estrogen-related receptors (ERR), orphan nuclear receptors that play critical roles in the transcription regulation of many nuclear-encoded mitochondrial proteins. All three ERRs (α, β and γ) increased the transcription of MAOs A and B; the effects were abolished by parkin, but not by its PD-linked mutants. Parkin bound to ERRs and increased their ubiquitination and degradation. In fibroblasts from PD patients with parkin mutations or brain slices from parkin knockout mice, degradation of ERRs was significantly attenuated. The results reveal the molecular mechanism by which parkin suppresses the transcription of MAOs to control oxidative stress induced by dopamine oxidation.
authors.affiliation: Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Ren
authors.forename: Houbo
authors.initials: H
authors.lastname: Jiang
authors.forename: Dingyuan
authors.initials: D
authors.lastname: Ma
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaso
authors.forename: Jian
authors.initials: J
authors.lastname: Feng
mesh_terms: D000818:Animals; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008995:Monoamine Oxidase / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D008995:Monoamine Oxidase; D011960:Receptors, Estrogen; D044767:Ubiquitin-Protein Ligases; D000097983:ERRalpha Estrogen-Related Receptor; C490918:ESRRB protein, human; C490917:ESRRG protein, human; C111567:parkin protein