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Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome
Open accessAbstract
Adults with Down syndrome (DS) develop Alzheimer neurofibrillary degeneration in the brain, but the underlying molecular mechanism is unknown. Here, we report that the presence of an extra copy of the dual‐specificity tyrosine‐phosphorylated and regulated kinase 1A ( Dyrk1A ) gene due to trisomy 21 resulted in overexpression of Dyrk1A and elevated kinase activity in DS brain. Dyrk1A phosphorylated tau at several sites, and these sites were hyperphosphory‐lated in adult DS brains. Phosphorylation of tau by Dyrk1A primed its further phosphorylation by glycogen synthase kinase‐3β (GSK‐3β). Dyrk1A‐induced tau phosphorylation inhibited tau's biological activity and promoted its self‐aggregation. In Ts65Dn mouse brain, an extra copy of the Dyrk1A gene caused increased expression and activity of Dyrk1A and resulted in increased tau phosphorylation. These findings strongly suggest a novel mechanism by which the overexpression of Dyrk1A in DS brain causes neurofibrillary degeneration via hyperphosphorylating tau. Liu, F., Liang, Z., Wegiel, J., Hwang, Y.‐W., Iqbal, K., Grundke‐Iqbal, I., Ramakrishna, N., Gong, C.‐X. Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome. FASEB J. 22, 3224–3233 (2008)
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“An approximate 1.5-fold increase in DYRK1A was found in homogenates from brains from human adults with DS and ~ 1.5-fold increase in DYRK1A from brain homogenates from 15-month-old Ts65Dn mice was observed (Liu et al., 2008).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Liu et al., 2008
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“An approximate 1.5-fold increase in DYRK1A was found in homogenates from brains from human adults with DS and ~ 1.5-fold increase in DYRK1A from brain homogenates from 15-month-old Ts65Dn mice was observed (Liu et al., 2008).”
From Sex-specific developmental alterations in DYRK1A expression in the brain of a Down syndrome mouse model (2024) · cites this paper as Liu et al., 2008
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Self-citationThe specificities of protein kinase inhibitors: an update
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“To verify the specificity of the assay, we added 10 M epigallocatechin-3-gallate (EGCG), a selective Dyrk1A inhibitor (22) into the assay mixture and found that EGCG inhibited 80% of the kinase activity in the brain extracts (Fig.”
MethodOccurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome
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Self-citationLiu, F., Grundke‐Iqbal, I., Iqbal, K., & Gong, C. (2005) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04391.x · Cited by 759
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Tau and neurodegenerative disease: the story so far
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Self-citationMechanisms of tau-induced neurodegeneration
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Self-citationA genetic cause of Alzheimer disease: mechanistic insights from Down syndrome
Wiseman, F. K., Al-Janabi, T., Hardy, J., Karmiloff-Smith, A., Nizetic, D., Tybulewicz, V. L. J., Fisher, E. M. C., & Strydom, A. (2015) · Nature Reviews Neuroscience · doi:10.1038/nrn3983 · Cited by 562
Metadata
- Authors
- Liu, F., Liang, Z., Wegiel, J., Hwang, Y., Iqbal, K., Grundke‐Iqbal, I., Ramakrishna, N., & Gong, C.
- Affiliations
- Department of Neurochemistry New York State Institute for Basic Research in Developmental Disabilities Staten Island New York USA
- Department of Developmental Neurobiology New York State Institute for Basic Research in Developmental Disabilities Staten Island New York USA
- Department of Molecular Biology New York State Institute for Basic Research in Developmental Disabilities Staten Island New York USA
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2008-05-28
- Volume
- 22
- Issue
- 9
- Pages
- 3224-3233
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC2518253
- OpenAlex
- W1986503994
- Cited by
- 272
- References
- 62
- Citations by year
- 2026: 19 · 2025: 16 · 2024: 18 · 2023: 17 · 2022: 20 · 2021: 18 · 2020: 13 · 2019: 13 · 2018: 11 · 2017: 23 · 2016: 8 · 2015: 11 · 2014: 15 · 2013: 16 · 2012: 9
- FWCI
- 10.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (AG027429, HD043960, HD038295, AG019158)
- Alzheimer's Association (IIRG-05-13095)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- DYRK1A, Down syndrome, neurofibrillary degeneration, tau hyperphosphorylation, glycogen synthase kinase-3β, kinase activity, Ts65Dn mouse model, Alzheimer's disease
- MeSH terms
- Glycogen Synthase Kinase 3 beta, Dyrk Kinases, Aged, Aged, 80 and over, Animals, Down Syndrome, Female, Humans, Male, Middle Aged, Nerve Degeneration, Phosphorylation, Protein-Tyrosine Kinases, Neurofibrillary Tangles, tau Proteins, Protein Serine-Threonine Kinases, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3, Mice
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