title: Parkin-dependent degradation of the F-box protein Fbw7β promotes neuronal survival in response to oxidative stress by stabilizing Mcl-1.
abstract: Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunction. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. PARK2, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease. Here, we present evidence for a neuronal ubiquitin ligase cascade involving parkin and the multisubunit ubiquitin ligase SCF(Fbw7β). Specifically, parkin targets the SCF substrate adapter Fbw7β for proteasomal degradation. Furthermore, we show that the physiological role of parkin-mediated regulation of Fbw7β levels is the stabilization of the mitochondrial prosurvival factor Mcl-1, an SCF(Fbw7β) target in neurons. We show that neurons depleted of parkin become acutely sensitive to oxidative stress due to an inability to maintain adequate levels of Mcl-1. Therefore, loss of parkin function through biallelic mutation of PARK2 may lead to death of dopaminergic neurons through unregulated SCF(Fbw7β)-mediated ubiquitylation-dependent proteolysis of Mcl-1.
authors.affiliation: Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA.
authors.forename: Susanna
authors.initials: S
authors.lastname: Ekholm-Reed
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Goldberg
authors.forename: Michael G
authors.initials: MG
authors.lastname: Schlossmacher
authors.forename: Steven I
authors.initials: SI
authors.lastname: Reed
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D004195:Disease Models, Animal; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability; D059748:Proteolysis; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513272:Fbxw7 protein, mouse; C579094:Mcl1 protein, mouse; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3