Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein

Accumulation of aggregated alpha-synuclein (alpha-syn) is believed to play a pivotal role in the pathophysiology of Parkinson's disease (PD) and other synucleinopathies. As a key constituent of Lewy pathology, more than 90% of alpha-syn in Lewy bodies is phosphorylated at serine-129 (pS129) and hence, it is used extensively as a marker for alpha-syn pathology. However, the exact role of pS129 remains controversial and the kinase(s) responsible for the phosphorylation have yet to be determined. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using an ex vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on alpha-syn aggregation, pS129 or inter-neuronal spreading of the aggregated alpha-syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble pS129 level in the nuclei. The same finding was replicated in an in vivo mouse model of templated alpha-syn aggregation and in human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129-phosphorylation of the soluble physiological fraction of alpha-syn. We also demonstrated that reduction of nuclear pS129 following PLK2 inhibition for a short time before sample collection improves the signal-to-noise ratio when quantifying pS129 aggregate pathology.

Automated summary

The study investigated the impact of PLK2 inhibition on alpha-synuclein phosphorylation, revealing that PLK2 inhibition reduces the nuclear soluble pS129 level. The findings suggest that PLK2 is likely involved in the S129 phosphorylation of the soluble physiological fraction of alpha-synuclein.