Parkin-Mediated Ubiquitination at the Synapse

Parkinson's disease (PD) involves the death of dopamine neurons in the midbrain and leads to devastating motor and functional impairment. Although treatment is available, its effectiveness diminishes over the long term. Hope for a more definitive treatment lies in basic biomedical research. Already, important advances have been made using molecular and genetic approaches. Until recently, genetics were not considered to be important in understanding PD. However, in the past six years alone, three genes have been identified, which cause familial forms of PD. Of these genes, "parkin" accounts for more cases than all the others combined. It is responsible for a young-onset familial form of the disease as well as certain non-familial cases. My laboratory is interested in understanding the normal function of parkin and how defects in parkin lead to PD. It appears that parkin functions as a key enzyme in the main system for protein degradation in the cell, the ubiquitin proteasome pathway. A hypothesis that we are pursuing is that defects in parkin function might lead to inefficient protein degradation and the accumulation of potentially toxic proteins within DA neurons. Understanding parkin function will undoubtedly enhance our understanding of the mechanisms of dopamine neuron death in PD.