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

An increase in alpha-synuclein levels due to gene duplications/triplications or impaired degradation is sufficient to trigger its aggregation and cause familial Parkinson disease (PD). Therefore, lowering alpha-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 alpha-synuclein autophagic degradation in a kinase activity-dependent manner. PLK2-mediated degradation of alpha-synuclein requires both phosphorylation at S129 and PLK2/alpha-synuclein complex formation. In a rat genetic model of PD, PLK2 overexpression reduces intraneuronal human a-synuclein accumulation, suppresses dopaminergic neurodegeneration, and reverses hemiparkinsonian motor impairments induced by alpha-synuclein overexpression. This PLK2-mediated neuroprotective effect is also dependent on PLK2 activity and a-synuclein phosphorylation. Collectively, our findings demonstrate that PLK2 is a previously undescribed regulator of alpha-synuclein turnover and that modulating its kinase activity could be a viable target for the treatment of synucleinopathies.