The interplay between parkin and alpha-synuclein; possible implications for the pathogenesis of Parkinson's disease

摘要

Parkin and alpha-synuclein (alpha-syn) are two key proteins involved in the pathophysiology of Parkinson's disease (PD). Oligomerization/aggregation and excessive secretion of a-syn contributes to PD through free radical stress, mitochondrial impairment, and synaptic dysfunction. Parkin, an E3 ubiquitin ligase, is considered to be a pleiotropic, neuroprotective protein that modulates metabolic turnover and the accumulation of alpha-syn. This is in addition to parkin's role in counteracting the more distant effects of alpha-syn on cellular survival by altering proteasomal, autophagic, and calpain-mediated protein degradation pathways that can reduce alpha-syn levels. Moreover, parkin regulates mitochondrial turnover, cell survival, and immune phenomena - processes that are all known to be disturbed in PD. In addition, parkin might have an impact on the spreading and propagation of alpha-syn by controlling its post-translational modifications. On the other hand, recent research has shown that alpha-syn oligomers affect the expression, post-translational modification, and activity of parkin. This review focuses on the molecular mechanisms of cross-talk between parkin and alpha-syn in PD. The physical and functional interactions between alpha-syn and parkin, which have been incompletely characterized to-date, may present a new therapeutic avenue in PD and related synucleinopathies. The development of effective, clinically feasible modulators may offer great hopes for the therapy of PD.