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.
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Publication status||Published - 8 Oct 2013|
- Adeno-associated virus
- Animal model
- Serum inducible kinase
ASJC Scopus subject areas