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

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  • Sara Elfarrash, Danish Research Institute of Translational Neuroscience DANDRITE, Mansoura University, Mansoura, MERC-Medical Experimental Research Center
  • ,
  • Nanna Møller Jensen
  • Nelson Ferreira
  • Sissel Ida Schmidt, Danish Hospital for Rheumatic Diseases, University Hospital of Southern Jutland, Sønderborg, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Hospital of Southern Jutland, University Hospital of Southern Denmark, Aabenraa, Denmark. Electronic address: Jprimdahl@danskgigthospital.dk.
  • ,
  • Emil Gregersen
  • Marie Vibeke Vestergaard, Danish Research Institute of Translational Neuroscience DANDRITE
  • ,
  • Sadegh Nabavi
  • Morten Meyer, Danish Hospital for Rheumatic Diseases, University Hospital of Southern Jutland, Sønderborg, Denmark; Department of Regional Health Research, University of Southern Denmark, Odense, Denmark; Hospital of Southern Jutland, University Hospital of Southern Denmark, Aabenraa, Denmark. Electronic address: Jprimdahl@danskgigthospital.dk.
  • ,
  • Poul Henning Jensen

Accumulation of aggregated alpha-synuclein (α-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 α-syn in Lewy bodies is phosphorylated at serine-129 (pS129) and hence, it is used extensively as a marker for α-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 α-syn aggregation, pS129 or inter-neuronal spreading of the aggregated α-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 α-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 α-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.

Original languageEnglish
JournalPLOS ONE
Volume16
Issue10
Pages (from-to)e0252635
ISSN1932-6203
DOIs
Publication statusPublished - 2021

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