Parkinson's disease (PD), a progressive neurodegenerative disorder that causes tremors, stiffness and impaired balance and coordination, results from the loss of dopamine-producing neurons in the midbrain. Defects in the ubiquitin-proteasome system and protein aggregation in Lewy bodies have typically been associated with the development of PD. A study in Nature Cell Biology now indicates that a proteasome-independent ubiquitylation pathway also contributes to the aetiology of this disease.
Parkin encodes an E3 ubiquitin ligase that is inactivated in ∼50% of early-onset PD cases. Edward Fon and colleagues showed that, in addition to targeting proteins for degradation, parkin can delay epidermal growth factor (EGF) receptor (EGFR) trafficking by ubiquitylating the endocytic scaffolding protein EPS15, and can promote signalling through phosphoinositide 3-kinase (PI3K)–Akt, an important pathway for neuronal survival.
The ubiquitin-like domain of wild-type parkin, but not of a PD-associated form, binds to the ubiquitin-interacting motif (UIM) of EPS15. This interaction is regulated by EGF, the addition ofwhich transiently increased the formation of a parkin–EPS15–EGFR complex and EPS15 ubiquitylation. The authors propose that intramolecular UIM–ubiquitin binding not only decreases the capability of EPS15 to induce EGFR internalization, but also prevents EPS15 from interacting with parkin, possibly explaining the transient nature of the complex.
Overexpression of parkin specifically reduced EGF uptake in COS-7 cells. Consistently, the rate of EGFR internalization was faster in mouse embryonic fibroblasts from parkin-knockout mice compared with wild-type mice. Small-interfering-RNA-mediated EPS15 knockdown did not further decrease the rate of EGFR endocytosis, indicating that EPS15 is required for the effect of parkin on receptor internalization.
...these findings are indicative of a novel mechanism through which parkin could prevent neurodegeneration.
Last, the authors showed that by decreasing receptor internalization, parkin also regulates EGF signalling via the PI3K–Akt pathway. EGF-induced Akt phosphorylation in synaptosomes from parkin-knockout mice was remarkably reduced compared with wild-type synaptosomes. Due to the positive role of Akt in neuronal survival, these findings are indicative of a novel mechanism through which parkincould preventneurodegeneration.
In addition, two studies in Nature have recently described a role for parkin in the maintenance of mitochondrial integrity in dopaminergic neurons. It will be interesting to determine whether particular parkin mutations affect specific aspects of parkin function. Therapeutic strategies that are aimed at these novel pathways could lead to better and more effective treatments for PD.
References
ORIGINAL RESEARCH PAPER
Fallon, L. et al. A regulated interaction with the UIM protein Eps15 implicates parkin in EGF receptor trafficking and PI(3)K–Akt signalling. Nature Cell Biol. 8, 834–848 (2006)
FURTHER READING
Park, J. et al. Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature 441, 1157–1161 (2006)
Clark, I. E. et al. Drosophila pink1 is required for mitochondrial function and interacts genetically with parkin. Nature 441, 1162–1166 (2006)
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Flight, M. Receptor traffic — parkin rules. Nat Rev Mol Cell Biol 7, 625 (2006). https://doi.org/10.1038/nrm2010
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DOI: https://doi.org/10.1038/nrm2010