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

Research output: Contribution to journalArticle

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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

Fingerprint

Synucleins
Lewy Bodies
Alzheimer Disease
Phosphorylation
Cell death
Down Syndrome
Cell Death
Phosphotransferases
Genes
Essential Genes
Neurogenesis
Human Chromosomes
Fibroblast Growth Factor 2
Chromosomes
Intellectual Disability
Protein-Tyrosine Kinases
Small Interfering RNA
Drosophila
Transfection
Parkinson Disease

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Eun, Joo Kim ; Jee, Young Sung ; Hyun, Jung Lee ; Rhim, Hyewhon ; Hasegawa, Masato ; Iwatsubo, Takeshi ; Do, Sik Min ; Kim, Jongsun ; Paik, Seung R. ; Kwang, Chul Chung. / Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation. In: Journal of Biological Chemistry. 2006 ; Vol. 281, No. 44. pp. 33250-33257.
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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.",
author = "Eun, {Joo Kim} and Jee, {Young Sung} and Hyun, {Jung Lee} and Hyewhon Rhim and Masato Hasegawa and Takeshi Iwatsubo and Do, {Sik Min} and Jongsun Kim and Paik, {Seung R.} and Kwang, {Chul Chung}",
year = "2006",
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Eun, JK, Jee, YS, Hyun, JL, Rhim, H, Hasegawa, M, Iwatsubo, T, Do, SM, Kim, J, Paik, SR & Kwang, CC 2006, 'Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation', Journal of Biological Chemistry, vol. 281, no. 44, pp. 33250-33257. https://doi.org/10.1074/jbc.M606147200

Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation. / Eun, Joo Kim; Jee, Young Sung; Hyun, Jung Lee; Rhim, Hyewhon; Hasegawa, Masato; Iwatsubo, Takeshi; Do, Sik Min; Kim, Jongsun; Paik, Seung R.; Kwang, Chul Chung.

In: Journal of Biological Chemistry, Vol. 281, No. 44, 03.11.2006, p. 33250-33257.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Dyrk1A phosphorylates α-synuclein and enhances intracellular inclusion formation

AU - Eun, Joo Kim

AU - Jee, Young Sung

AU - Hyun, Jung Lee

AU - Rhim, Hyewhon

AU - Hasegawa, Masato

AU - Iwatsubo, Takeshi

AU - Do, Sik Min

AU - Kim, Jongsun

AU - Paik, Seung R.

AU - Kwang, Chul Chung

PY - 2006/11/3

Y1 - 2006/11/3

N2 - 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.

AB - 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.

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