Phosphorylation of synucleins by members of the polo-like kinase family

Martial K. Mbefo, Katerina E. Paleologou, Ahmed Boucharaba, Abid Oueslati, Heinrich Schell, Margot Fournier, Diana Olschewski, Guowei Yin, Markus Zweckstetter, Eliezer Masliah, Philipp J. Kahle, Harald Hirling, Hilal A. Lashuel

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Abstract

Phosphorylation of α-synuclein (α-syn) at Ser-129 is a hallmark of Parkinson disease and related synucleinopathies. However, the identity of the natural kinases and phosphatases responsible for regulating α-syn phosphorylation remain unknown. Here we demonstrate that three closely related members of the human Polo-like kinase (PLK) family (PLK1, PLK2, and PLK3) phosphorylate α-syn and β-syn specifically at Ser-129 and Ser-118, respectively. Unlike other kinases reported to partially phosphorylate α-syn at Ser-129 in vitro, phosphorylation by PLK2 and PLK3 is quantitative (>95% conversion). Only PLK1 and PLK3 phosphorylate β-syn at Ser-118, whereas no phosphorylation of γ-syn was detected by any of the four PLKs (PLK1 to -4). PLK-mediated phosphorylation was greatly reduced in an isolated C-terminal fragment (residues 103-140) of α-syn, suggesting substrate recognition via the N-terminal repeats and/or the non-amyloid component domain of α-syn. PLKs specifically co-localized with phosphorylated Ser-129 (Ser(P)-129) α-syn in various subcellular compartments (cytoplasm, nucleus, and membranes) of mammalian cell lines and primary neurons as well as in α-syn transgenic mice, especially cortical brain areas involved in synaptic plasticity. Furthermore, we report that the levels of PLK2 are significantly increased in brains of Alzheimer disease and Lewy body disease patients. Taken together, these results provide biochemical and in vivo evidence of α-syn and β-syn phosphorylation by specific PLKs. Our results suggest a need for further studies to elucidate the potential role of PLK-syn interactions in the normal biology of these proteins as well as their involvement in the pathogenesis of Parkinson disease and other synucleinopathies.

Original languageEnglish
Pages (from-to)2807-2822
Number of pages16
JournalJournal of Biological Chemistry
Volume285
Issue number4
DOIs
Publication statusPublished - 22 Jan 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Mbefo, M. K., Paleologou, K. E., Boucharaba, A., Oueslati, A., Schell, H., Fournier, M., Olschewski, D., Yin, G., Zweckstetter, M., Masliah, E., Kahle, P. J., Hirling, H., & Lashuel, H. A. (2010). Phosphorylation of synucleins by members of the polo-like kinase family. Journal of Biological Chemistry, 285(4), 2807-2822. https://doi.org/10.1074/jbc.M109.081950