Parkin Is a Component of an SCF-like Ubiquitin Ligase Complex and Protects Postmitotic Neurons from Kainate Excitotoxicity

Abstract

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.

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

“…7 Immunoblotting analyses revealed that cyclin E protein expression in HT29 cells increased in response to EGF treatment, and peaked 18 hr after stimulation. At 20 hr after EGF stimulation, when EGF-mediated Parkin protein expression was at its peak, the expression levels of cyclin E protein were substantially reduced (Fig.…”

“…4 Several putative candidate substrates of Parkin-mediated proteolysis have been identified, including a-synphilin, a-synuclein interacting protein, synphilin-1 and Pael-R. 5,6 Recently, it was revealed that deficiency of Parkin potentiates the accumulation of cyclin E protein in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate, suggesting that the cell cycle regulator, cyclin E, is a putative substrate of the Parkin ubiquitin ligase complex in neurons. 7 Since Parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism, one form of familial Parkinson disease, 8 attention has been focused on unveiling the role of Parkin in neurons. The expression and regulation of Parkin in epithelial cells as well as the role of Parkin in cell cycle regulation, however, has not been clarified.…”

Parkin-mediated Monoubiquitination of the PDZ Protein PICK1 Regulates the Activity of Acid-sensing Ion Channels

“…The ensuing accumulation of parkin substrates is believed, in turn, to induce the cellular toxicity and dopamine neuron loss seen in PD. Although numerous parkin substrates have been identified (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Corti et al, 2003;Staropoli et al, 2003), there is still controversy as to which of these accumulate in the brains of parkin knockout (KO) mice (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Ko et al, 2005;Perez and Palmiter, 2005;Periquet et al, 2005) and as to their respective roles in the pathogenesis of PD (Cookson, 2005;Moore et al, 2005).…”

“…The ensuing accumulation of parkin substrates is believed, in turn, to induce the cellular toxicity and dopamine neuron loss seen in PD. Although numerous parkin substrates have been identified (Zhang et al, 2000;Chung et al, 2001;Imai et al, 2001;Corti et al, 2003;Staropoli et al, 2003), there is still controversy as to which of these accumulate in the brains of parkin knockout (KO) mice (Goldberg et al, 2003;Itier et al, 2003;Von Coelln et al, 2004;Ko et al, 2005;Perez and Palmiter, 2005;Periquet et al, 2005) and as to their respective roles in the pathogenesis of PD (Cookson, 2005;Moore et al, 2005).In addition to its traditional role, Ub can serve as a reversible posttranslational modification that regulates the function of tagged proteins without necessarily leading to their destruction by the proteasome (Hicke and Dunn, 2003;Mukhopadhyay and Riezman, 2007). Depending on the length and architecture of the Ub chain, ubiquitination has been implicated in a variety of cellular functions as diverse as signal transduction, transcription, and membrane trafficking (Mukhopadhyay and Riezman, 2007).…”

Tumorigenesis and neurodegeneration: two sides of the same coin?

“…One candidate substrate in this context is cyclin E, which is upregulated by gene amplification (64) and by other mechanisms (65,66) in breast, ovarian and other tumors. (4,67) Notably, F-box/WD40 repeat protein 7 (Fbw7/ Sel-10), itself a component of a parkin-associated ubiquitin ligase complex, (53) is sporadically mutated in several breast and endometrial tumors showing elevated cyclin E protein levels. (68,69) Thus, deficiency of parkin, like deficiency of ATM, may represent a double-edged sword, leading to degeneration of post-mitotic neurons and contributing to tumorigenesis in mitotically active cells.…”