Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation

Joo Kim Eun, Young Sung Jee, Jung Lee Hyun, Hyewhon Rhim, Masato Hasegawa, Takeshi Iwatsubo, Sik Min Do, Jongsun Kim, Seung R. Paik, Chul Chung Kwang

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Abstract

Lewy bodies (LBs) are pathological hallmarks of Parkinson disease (PD) but also occur in Alzheimer disease (AD) and dementia of LBs. α-Synuclein, the major component of LBs, is observed in the brain of Down syndrome (DS) patients with AD. Dyrk1A, a dual specificity tyrosine-regulated kinase (Dyrk) family member, is the mammalian ortholog of the Drosophila minibrain (Mnb) gene, essential for normal postembryonic neurogenesis. The Dyrk1A gene resides in the human chromosome 21q22.2 region, which is associated with DS anomalies, including mental retardation. In this study, we examined whether Dyrk1A interacts with α-synuclein and subsequently affects intracellular α-synuclein inclusion formation in immortalized hippocampal neuronal (H19-7) cells. Dyrk1A selectively binds to α-synuclein in transformed and primary neuronal cells. α-Synuclein overexpression, followed by basic fibroblast growth factor-induced neuronal differentiation, resulted in cell death. We observed that accompanying cell death was increased α-synuclein phosphorylation and intracytoplasmic aggregation. In addition, the transfection of kinase-inactive Dyrk1A or Dyrk1A small interfering RNA blocked α-synuclein phosphorylation and aggregate formation. In vitro kinase assay o fanti-Dyrk1A immunocomplexes demonstrated that Dyrk1A could phosphorylate α-synuclein at Ser-87. Furthermore, aggregates formed by phosphorylated α-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type α-synuclein. These findings suggest α-synuclein inclusion formation regulated by Dyrk1A, potentially affecting neuronal cell viability.

Original languageEnglish
Pages (from-to)33250-33257
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number44
DOIs
Publication statusPublished - 2006 Nov 3

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Eun, J. K., Jee, Y. S., Hyun, J. L., Rhim, H., Hasegawa, M., Iwatsubo, T., Do, S. M., Kim, J., Paik, S. R., & Kwang, C. C. (2006). Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation. Journal of Biological Chemistry, 281(44), 33250-33257. https://doi.org/10.1074/jbc.M606147200