Dissecting the Molecular Pathway Involved in PLK2 Kinase-mediated α-Synuclein-selective Autophagic Degradation

J Biol Chem. 2017 Mar 3;292(9):3919-3928. doi: 10.1074/jbc.M116.759373. Epub 2017 Jan 30.

Abstract

Increasing lines of evidence support the causal link between α-synuclein (α-syn) accumulation in the brain and Parkinson's disease (PD) pathogenesis. Therefore, lowering α-syn protein levels may represent a viable therapeutic strategy for the treatment of PD and related disorders. We recently described a novel selective α-syn degradation pathway, catalyzed by the activity of the Polo-like kinase 2 (PLK2), capable of reducing α-syn protein expression and suppressing its toxicity in vivo However, the exact molecular mechanisms underlying this degradation route remain elusive. In the present study we report that among PLK family members, PLK3 is also able to catalyze α-syn phosphorylation and degradation in living cells. Using pharmacological and genetic approaches, we confirmed the implication of the macroautophagy on PLK2-mediated α-syn turnover, and our observations suggest a concomitant co-degradation of these two proteins. Moreover, we showed that the N-terminal region of α-syn is important for PLK2-mediated α-syn phosphorylation and degradation and is implicated in the physical interaction between the two proteins. We also demonstrated that PLK2 polyubiquitination is important for PLK2·α-syn protein complex degradation, and we hypothesize that this post-translational modification may act as a signal for the selective recognition by the macroautophagy machinery. Finally, we observed that the PD-linked mutation E46K enhances PLK2-mediated α-syn degradation, suggesting that this mutated form is a bona fide substrate of this degradation pathway. In conclusion, our study provides a detailed description of the new degradation route of α-syn and offers new opportunities for the development of therapeutic strategies aiming to reduce α-syn protein accumulation and toxicity.

Keywords: protein degradation; protein kinase; protein phosphorylation; ubiquitin; α-synuclein (a-synuclein).

MeSH terms

  • Autophagy*
  • Catalysis
  • HEK293 Cells
  • Humans
  • Mutation
  • Phosphorylation
  • Plasmids / metabolism
  • Protein Interaction Mapping
  • Protein Processing, Post-Translational
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteolysis
  • Serine / chemistry
  • Tumor Suppressor Proteins
  • Ubiquitin / chemistry
  • alpha-Synuclein / metabolism*

Substances

  • Tumor Suppressor Proteins
  • Ubiquitin
  • alpha-Synuclein
  • Serine
  • PLK3 protein, human
  • PLK2 protein, human
  • Protein Serine-Threonine Kinases