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

Elfarrash, S.; Jensen, N. M.; Ferreira, N.; Schmidt, S. I.; Gregersen, E.; Vestergaard, M. V.; Nabavi, S.; Meyer, M.; Jensen, P. H.

doi:10.1101/2021.05.21.445104

bioRxiv · 10.1101/2021.05.21.445104

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

Elfarrash, S.·Jensen, N. M.·Ferreira, N.·Schmidt, S. I.·Gregersen, E.·Vestergaard, M. V.·Nabavi, S.·Meyer, M.·Jensen, P. H.

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Abstract

Accumulation of aggregated alpha-synuclein (-syn) is believed to play a pivotal role in the pathophysiology of Parkinsons disease (PD) and other synucleinopathies. -Syn is a key constituent protein of Lewy pathology, and -syn phosphorylated at serine-129 (pS129) constitutes more than 90% of -syn in Lewy bodies and hence, it is used extensively as a pathological marker for the aggregated form of -syn. However, the exact role of pS129 remains controversial as well as the kinase(s) responsible for the phosphorylation. In this study, we investigated the effect of Polo-like kinase 2 (PLK2) inhibition on formation of pS129 using ex-vivo organotypic brain slice model of synucleinopathy. Our data demonstrated that PLK2 inhibition has no effect on -syn aggregation, pS129 or inter-neuronal spreading of the aggregated -syn seen in the organotypic slices. Instead, PLK2 inhibition reduced the soluble nuclear pS129 level confined in the nuclei. The same finding was replicated in an in-vivo mouse models of templated -syn aggregation and human dopaminergic neurons, suggesting that PLK2 is more likely to be involved in S129 phosphorylation of soluble non-pathology related fraction of -syn. We also demonstrated that reduction of nuclear pS129 but not the aggregates specific pS129 following PLK2 inhibition for a short time before sample collection improves the signal to noise ratio when quantifying pS129 aggregate pathology.

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Elfarrash, S., Jensen, N. M., Ferreira, N., Schmidt, S. I., Gregersen, E., Vestergaard, M. V., Nabavi, S., Meyer, M., Jensen, P. H.. 2021-05-21. Polo-like kinase 2 inhibition reduces serine-129 phosphorylation of physiological nuclear alpha-synuclein but not of the aggregated alpha-synuclein. https://doi.org/10.1101/2021.05.21.445104

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