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Edward A Fon"The Role of Parkin and Ubiquitination at the Synapse"

Abstract :


P
arkinson’s disease leads to devastating motor and functional impairment. Although treatment is available, its effectiveness diminishes over the long term. My laboratory is interested in the molecular events leading to the degeneration of midbrain dopamine neurons in Parkinson's disease. Not very long ago, genetics was not thought to be important in Parkinson’s disease. However, in the past decade, several genes have been identified, which cause familial forms of the disease. Of these genes, "parkin" accounts for more cases than all the others combined. Parkin functions as an E3 ubiquitin ligase, a key enzyme in the ubiquitin proteasome system, the main protein degradation pathway in the cell. Ubiquitin, a small protein, can be covalently attached to target proteins, thereby marking them for degradation by the 26S proteasome. E3 ubiquitin-ligases, such as parkin, are involved in target protein recognition, thereby regulating and conferring specificity to ubiquitination.

We have been working on trying to understand the normal function of parkin and how defects in parkin lead to Parkinson’s disease. We have shown that parkin is localized at the synapse, in the postsynaptic density, where it is part of a large protein complex that includes the NMDA receptor and several scaffolding proteins. We also showed that parkin mediates the ubiquitination of synaptic proteins within this complex. Considering that ubiquitination has been implicated in various aspects of neuronal function, we believe that parkin might control the degradation of key synaptic proteins and thereby regulate synaptic transmission and plasticity.

Traditionally, proteins that are modified with ubiquitin are rapidly degraded by the proteasome. In addition to this role in protein degradation, ubiquitin can serve as a reversible post-translational modification that regulates the function of ubiquitin-tagged proteins without necessarily leading to their degradation. Our recent work suggests that parkin may function in such non-traditional ubiquitination pathways. We find that parkin interacts with Eps15, a protein involved in Epidermal Growth Factor Receptor trafficking. We believe that by ubiquitinating Eps15, parkin regulates growth factor endocytosis and signaling. Considering the potential for growth factors to influence neuronal survival, we believe that further work in this area will provide important clues about the mechanisms of dopamine neuron death in Parkinson’s disease and potentially lead to innovative new therapeutic strategies.

Selected publications

Croft BG, Fortin G, Corera AT, Beaudet A, Edwards RH, Trudeau LE, Fon EA.
Normal biogenesis and cycling of synaptic vesicles in dopamine neurons of VMAT2 knockout mice. Mol. Biol. Cell 2005; 16(1):306-15.
Kalia SK, Lee S, Liu L, Crocker SJ, Thorarinsdottir TE, Smith PD, Glover JR, Fon EA, Park DS, Lozano AM.
BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.
Neuron 2004; 44(6):931-45.
Fallon L, Moreau F, Croft BG, Labib N, Gu WJ, Fon EA.
Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain.
J Biol Chem. 2002; 277(1):486-91.
Larsen KE, Fon EA, Hastings TG, Edwards RH, and Sulzer D.
Methamphetamine-induced degeneration of dopaminergic neurons involves autophagy and upregulation of dopamine synthesis.
J. Neurosc. 2002; 22(20):8951-60.

Stephane Oliet