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

Henryk Jęśko,Anna M Lenkiewicz,Anna Wilkaniec,Agata Adamczyk

doi:10.21307/ane-2019-026

Abstract

Parkin and alpha-synuclein (α-syn) are two key proteins involved in the pathophysiology of Parkinson's disease (PD). Oligomerization/aggregation and excessive secretion of α-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 α-syn. This is in addition to parkin's role in counteracting the more distant effects of α-syn on cellular survival by altering proteasomal, autophagic, and calpain-mediated protein degradation pathways that can reduce α-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 α-syn by controlling its post-translational modifications. On the other hand, recent research has shown that α-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 α-syn in PD. The physical and functional interactions between α-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 the rapy of PD.

Highlights

Parkinson’s disease (PD) is one of the most com‐ mon age‐related neurodegenerative disorders
Parthanatos involves proteins that are typically engaged in DNA repair, in‐ cluding poly(ADP‐ribose) polymerase (PARP1) or 8‐oxoG glycosylase1 (OGG1), These proteins lead to PAR‐medi‐ ated signaling from the nucleus to the mitochondria, triggering release of apoptosis‐inducing factor (AIF), chromatin condensation and large scale fragmentation, and cell death
Parkin is extensively engaged in protein degrada‐ tion pathways, and as such may offer significant thera‐ peutic potential. α‐syn levels may be controlled by par‐ kin‐dependent proteasomal degradation

Summary

Introduction

Parkinson’s disease (PD) is one of the most com‐ mon age‐related neurodegenerative disorders. Whereas loss of parkin activity leads to accumulation of non‐ubiquiti‐ nated forms of α‐syn (Shimura et al, 2001), compounds that augment proteasomal α‐syn degradation have beneficial neuroprotective effects and are considered to have a potential therapeutic application in PD (Jęśko et al, 2017; Li et al, 2018).

Results

Conclusion