Alterations in the solubility and intracellular localization of parkin by several familial Parkinson's disease-linked point mutations

Mutations in the parkin gene, which encodes a ubiquitin ligase, are currently recognized as the main contributor to familial forms of Parkinson's disease (PD). A simple assumption about the effects of PD-linked mutations in parkin is that they impair or ablate the enzyme activity. However, a number of recent studies, including ours, have indicated that many disease-linked point mutants of parkin retain substantial catalytic activity. To understand how the plethora of mutations on parkin contribute to its dysfunction, we have conducted a systematic analysis of a significant number of parkin point mutants (22 in total), which represent the majority of parkin missense/nonsense mutations reported to date. We found that more than half of these mutations, including many located outside of the parkin RING fingers, produce alteration in the solubility of parkin which influences its detergent extraction property. This mutation-mediated alteration in parkin solubility is also associated with its propensity to form intracellular, aggresome-like, protein aggregates. However, they do not represent sites where parkin substrates become sequestered. As protein aggregation sequesters the functional forms away from their normal sites of action, our results suggest that alterations in parkin solubility and intracellular localization may underlie the molecular basis of the loss of function caused by several of its mutations.