How does parkin ligate ubiquitin to Parkinson's disease?

Recessive mutations in the human PARKIN gene are the most common cause of hereditary parkinsonism, which arises from the degeneration of dopaminergic neurons in the substantia nigra. However, the molecular mechanisms by which the loss of parkin causes dopaminergic neurodegeneration are not well understood. Parkin is an enzyme that ubiquitinates several candidate substrate proteins and thereby targets them for proteasomal degradation. Hypothesis‐driven searches have led to the discovery of aggregation‐prone protein substrates of parkin. Moreover, the enzyme is upregulated when under unfolded protein stress. Thus, loss‐of‐function mutations of parkin might impair the removal of potentially toxic protein aggregates. However, the limited neuropathological information that is available from parkin‐proven patients, as well as the recent knockout of the parkin gene in fruit flies and mice, may indicate a more complex disease mechanism, possibly involving the misfolding of parkin itself or of additional substrates. The risk factors that predispose dopaminergic neurons to degenerate on parkin failure are yet to be identified.