Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation

Topic: Brain proteins, microglia and lab models

Lewy bodies (LBs) are pathological hallmarks of Parkinson disease (PD) but also occur in Alzheimer disease (AD) and dementia of LBs. Alpha-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 alpha-synuclein and subsequently affects intracellular alpha-synuclein inclusion formation in immortalized hippocampal neuronal (H19-7) cells. Dyrk1A selectively binds to alpha-synuclein in transformed and primary neuronal cells. Alpha-synuclein overexpression, followed by basic fibroblast growth factor-induced neuronal differentiation, resulted in cell death. We observed that accompanying cell death was increased alpha-synuclein phosphorylation and intracytoplasmic aggregation. In addition, the transfection of kinase-inactive Dyrk1A or Dyrk1A small interfering RNA blocked alpha-synuclein phosphorylation and aggregate formation. In vitro kinase assay of anti-Dyrk1A immunocomplexes demonstrated that Dyrk1A could phosphorylate alpha-synuclein at Ser-87. Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein. These findings suggest alpha-synuclein inclusion formation regulated by Dyrk1A, potentially affecting neuronal cell viability.

Key findings

• The Dyrk1A gene resides in the human chromosome 21q22.2 region, which is associated with DS anomalies, including mental retardation.
• We observed that accompanying cell death was increased alpha-synuclein phosphorylation and intracytoplasmic aggregation.
• In vitro kinase assay of anti-Dyrk1A immunocomplexes demonstrated that Dyrk1A could phosphorylate alpha-synuclein at Ser-87.
• Furthermore, aggregates formed by phosphorylated alpha-synuclein have a distinct morphology and are more neurotoxic compared with aggregates composed of unmodified wild type alpha-synuclein.
• These findings suggest alpha-synuclein inclusion formation regulated by Dyrk1A, potentially affecting neuronal cell viability.

Why it matters

In neuronal cell experiments, the Dyrk1A enzyme was found to bind and phosphorylate alpha-synuclein at Ser-87, and blocking Dyrk1A reduced this phosphorylation and aggregate formation. These are cell-based laboratory findings, and the study does not test any treatment in people or in living animals.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m606147200
• PubMed: 16959772
• Original source →
• Free full text: Journal of Biological Chemistry →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{kim2006-16959772,
  author  = {Kim, E. J. and Sung, J. Y. and Lee, H. J. and Rhim, H. and Hasegawa, M. and Iwatsubo, T. and Min do, S. and Kim, J. and others},
  title   = {{Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation}},
  journal = {The Journal of biological chemistry},
  year    = {2006},
  doi     = {10.1074/jbc.m606147200},
  pmid    = {16959772},
  url     = {https://doi.org/10.1074/jbc.m606147200}
}

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions Science (New York, N.Y.) · 2000-11-01 · usefulness score 59/100 · Lewy body dementia
• Down syndrome phenotypes: the consequences of chromosomal imbalance Proceedings of the National Academy of Sciences of the United States of America · 1994-05-01 · usefulness score 52/100 · Down syndrome and Alzheimer's
• Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models Neurobiology of disease · 2005-11-01 · usefulness score 44/100 · Down syndrome and Alzheimer's

Later studies that cite this one

4 studies in the alzhub library list this one in their references.

• Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2008-05-28 · usefulness score 46/100 · Down syndrome and Alzheimer's
• Link between DYRK1A overexpression and several-fold enhancement of neurofibrillary degeneration with 3-repeat tau protein in Down syndrome Journal of neuropathology and experimental neurology · 2011-01-01 · usefulness score 43/100 · Down syndrome and Alzheimer's
• The role of DYRK1A in neurodegenerative diseases The FEBS journal · 2010-12-13 · usefulness score 43/100 · Down syndrome and Alzheimer's
• The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4 Neuroscience · 2008-10-01 · usefulness score 42/100 · Down syndrome and Alzheimer's

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