Figure 1. Proposed hypothesis of Parkin inactivation and subsequent neurodegeneration based on recent findings. The function of Parkin can be disturbed by four different factors. (a) Extracellular stress, inflammation, and insufficient neurotrophic factors can activate caspases that degrade Parkin [33. and 34.]. (b) Protein inclusions, such as LBs, resulting from impairment of proteasome activity might sequester Parkin thereby eliminating its activity, although there is discrepancy among the results of immunostaining in LBs with different Parkin antibodies [17., 30., 31. and 39.•]. (c) Oxidative stress within dopaminergic neurons has been suspected to be involved in PD, as an accumulation of iron is frequently observed in areas of degeneration in PD. Reactive oxidants, as well as dopamine/dopa-quinones, might modify a cluster of cysteine residues (represented by ‘C’) responsible for the E3 activity of Parkin, thus resulting in the precipitation of Parkin [22.• and 23.]. Increased levels of intracellular dopamine and dopamine metabolites due to inactivation of Parkin might further perpetuate adduct formation with the cysteine residues of Parkin [42.•• and 43.•]. (d) Genetic mutations of the parkin gene, among other factors, might disturb Parkin function, resulting in an accumulation of Parkin substrates and subsequent neurodegeneration. The substrates of mammalian Parkin might differ from those of fly Parkin, such that a deficiency of Parkin might have different effects in the two species [25.•].

Table 1. Reported substrates of Parkin.

Common features or binding motifs have not been identified among these reported substrates of Parkin. Some of them have been observed within LBs or Lewy neuritis (‘+’ and ‘−’ mean immunopositive and immunonegative, respectively, ‘N.D.’ indicates not determined). This finding suggests that Parkin dysfunction might be involved in some part of PD as well as AR-JP. ‘Y’ and ‘I’ in methods of identification indicate yeast two-hybrid screening and immunoprecipitation (or pull-down)/western blot assay, respectively.