Polo-like kinase 2 regulates selective autophagic ?-synuclein clearance and suppresses its toxicity in vivo.

ABSTRACT: An increase in ?-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering ?-synuclein levels represents a viable therapeutic strategy for the treatment of PD and related synucleinopathies. Here, we report that Polo-like kinase 2 (PLK2), an enzyme up-regulated in synucleinopathy-diseased brains, interacts with, phosphorylates and enhances ?-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of ?-synuclein requires both phosphorylation at S129 and PLK2/?-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human ?-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by ?-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and ?-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of ?-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies.

SUBMITTER: Oueslati A 

PROVIDER: S-EPMC3799334 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature