Parkin is a component of an SCF-like ubiquitin ligase complex and protects postmitotic neurons from kainate excitotoxicity.
Mutations in parkin, which encodes a RING domain protein associated with ubiquitin ligase activity, lead to autosomal recessive Parkinson's disease characterized by midbrain dopamine neuron loss. Here we show that parkin functions in a multiprotein ubiquitin ligase complex that includes the F-box/WD repeat protein hSel-10 and Cullin-1. HSel-10 serves to target the parkin ubiquitin ligase activity to cyclin E, an hSel-10-interacting protein previously implicated in the regulation of neuronal apoptosis. Consistent with the notion that cyclin E is a substrate of the parkin ubiquitin ligase complex, parkin deficiency potentiates the accumulation of cyclin E in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate and promotes their apoptosis. Furthermore, parkin overexpression attenuates the accumulation of cyclin E in toxin-treated primary neurons, including midbrain dopamine neurons, and protects them from apoptosis.
Staropoli
John F
JF
Department of Pathology, Center for Neurobiology and Behavior, Taub Institute, College of Physicians and Surgeons, Columbia University, 15-403, 630 West 168th Street, New York, NY 10032, USA.
McDermott
Caroline
C
Martinat
Cécile
C
Schulman
Brenda
B
Demireva
Elena
E
Abeliovich
Asa
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D007608:Kainic Acid / Q000633:toxicity*; D008025:Ligases / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008938:Mitosis / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010453:Peptide Synthases / Q000096:biosynthesis* / Q000235:genetics; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases
D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases; D010453:Peptide Synthases; D007608:Kainic Acid