Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome

Topic: Brain proteins, microglia and lab models

Two groups of tau, 3R- and 4R-tau, are generated by alternative splicing of tau exon 10. Normal adult human brain expresses equal levels of them. Disruption of the physiological balance is a common feature of several tauopathies. Very early in their life, individuals with Down syndrome (DS) develop Alzheimer-type tau pathology, the molecular basis for which is not fully understood. Here, we demonstrate that Dyrk1A, a kinase encoded by a gene in the DS critical region, phosphorylates alternative splicing factor (ASF) at Ser-227, Ser-234, and Ser-238, driving it into nuclear speckles and preventing it from facilitating tau exon 10 inclusion. The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration. Imbalance of 3R- and 4R-tau in DS brain by Dyrk1A-induced dysregulation of alternative splicing factor-mediated alternative splicing of tau exon 10 represents a novel mechanism of neurofibrillary degeneration and may help explain early onset tauopathy in individuals with DS.

@article{shi2008-18658135,
  author  = {Shi, J. and Zhang, T. and Zhou, C. and Chohan, M. O. and Gu, X. and Wegiel, J. and Zhou, J. and Hwang, Y. W. and others},
  title   = {{Increased dosage of Dyrk1A alters alternative splicing factor (ASF)-regulated alternative splicing of tau in Down syndrome}},
  journal = {The Journal of biological chemistry},
  year    = {2008},
  doi     = {10.1074/jbc.m802645200},
  pmid    = {18658135},
  url     = {https://doi.org/10.1074/jbc.m802645200}
}

Key findings

• The increased dosage of Dyrk1A in DS brain due to trisomy of chromosome 21 correlates to an increase in 3R-tau level, which on abnormal hyperphosphorylation and aggregation of tau results in neurofibrillary degeneration.

Why it matters

This laboratory work shows that extra Dyrk1A, as occurs in Down syndrome, drives alternative splicing of tau toward more 3R-tau, which the authors link to neurofibrillary degeneration. It proposes a mechanism for early tau pathology but tests no treatment, cure or prevention.

Study details

• Evidence strengthLow

Read the original

• DOI: 10.1074/jbc.m802645200
• PubMed: 18658135
• 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).

Studies this one cites

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

• Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17 Nature · 1998-06-01 · usefulness score 64/100 · Lewy body dementia
• Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome Annals of Neurology · 1985-03-01 · usefulness score 56/100 · Down syndrome and Alzheimer's
• Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements Proceedings of the National Academy of Sciences of the United States of America · 1999-05-01 · usefulness score 51/100 · Lewy body dementia
• Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform Neuron · 1999-11-01 · usefulness score 50/100 · Lewy body dementia
• Developmental abnormalities and age-related neurodegeneration in a mouse model of Down syndrome Proceedings of the National Academy of Sciences of the United States of America · 1996-11-01 · usefulness score 49/100 · Down syndrome and Alzheimer's
• Tau pathology in Alzheimer disease and other tauopathies Biochimica et biophysica acta · 2005-01-01 · usefulness score 49/100 · Lewy body dementia
• Mutations causing neurodegenerative tauopathies Biochimica et biophysica acta · 2005-01-01 · usefulness score 46/100 · Risk factors
• 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
• Amyloid Oligomers Exacerbate Tau Pathology in a Mouse Model of Tauopathy Neurodegenerative Diseases · 2012-07-10 · usefulness score 40/100 · Laboratory science

Later studies that cite this one

11 studies in the alzhub library list this one in their references. Showing the 8 highest-scoring.

• A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome Nature reviews. Neuroscience · 2015-08-05 · usefulness score 52/100 · Risk factors
• Mechanisms of tau-induced neurodegeneration Acta neuropathologica · 2009-01-30 · usefulness score 52/100 · Brain scans and imaging
• Tau and neurodegenerative disease: the story so far Nature reviews. Neurology · 2015-12-04 · usefulness score 49/100 · Lewy body dementia
• Tau in Alzheimer disease and related tauopathies Current Alzheimer research · 2010-12-01 · usefulness score 49/100 · Lewy body dementia
• A novel DYRK1A (dual specificity tyrosine phosphorylation-regulated kinase 1A) inhibitor for the treatment of Alzheimer's disease: effect on Tau and amyloid pathologies in vitro Journal of neurochemistry · 2015-01-26 · usefulness score 45/100 · 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
• Hyperphosphorylation-induced tau oligomers Frontiers in neurology · 2013-08-15 · usefulness score 42/100 · Down syndrome and Alzheimer's

Related studies in Down syndrome and Alzheimer's

• Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing Journal of medicinal chemistry · 2011-05-26 · usefulness score 36/100
• Lens defects and age-related fiber cell degeneration in a mouse model of increased AbetaPP gene dosage in Down syndrome The American journal of pathology · 2002-12-01 · usefulness score 34/100
• DYRK1A, a Dosage-Sensitive Gene Involved in Neurodevelopmental Disorders, Is a Target for Drug Development in Down Syndrome Frontiers in behavioral neuroscience · 2016-06-03 · usefulness score 40/100
• Leucettinib-21 decreases dosage effects of DYRK1A in human trisomy 21 iPSC-derived neural cells bioRxiv · 2026-02-05 · usefulness score 16/100
• Neuropathological measures of increased tau phosphorylation across the Down syndrome lifespan Acta neuropathologica · 2026-03-22 · usefulness score 48/100
• Increased levels of tau-like protein in patients with Down syndrome Neuroscience letters · 1999-11-01 · usefulness score 29/100

Also tagged “down”

527 studies in the library carry the topic tag “down”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 527 tagged studies.

• Patterns of depressive symptoms and social relating behaviors differ over time from other behavioral domains for young people with Down syndrome Medicine · 2015-05-01 · usefulness score 45/100 · Down syndrome and Alzheimer's
• Novel SNX13 Frameshift Variant in an Individual with Developmental Delay Cytogenetic and genome research · 2021-12-08 · usefulness score 32/100 · Down syndrome and Alzheimer's
• [Effect of the chronic treatment with L-acetylcarnitine in Down's syndrome] La Clinica terapeutica · 1994-02-01 · usefulness score 30/100 · Down syndrome and Alzheimer's

Similar studies

• DYRK1A-mediated hyperphosphorylation of Tau. A functional link between Down syndrome and Alzheimer disease 2007 · Down syndrome and Alzheimer's
• Dyrk1A phosphorylates alpha-synuclein and enhances intracellular inclusion formation 2006 · Down syndrome and Alzheimer's
• The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease 2007 · Genetics
• DYRK1A and Activity-Dependent Neuroprotective Protein Comparative Diagnosis Interest in Cerebrospinal Fluid and Plasma in the Context of Alzheimer-Related Cognitive Impairment in Down Syndrome Patients 2022 · Biomarkers
• Constitutive Dyrk1A is abnormally expressed in Alzheimer disease, Down syndrome, Pick disease, and related transgenic models 2005 · Down syndrome and Alzheimer's
• Impact of Triplicated DYRK1A on Neurogenesis and Intellectual Disability in Down Syndrome and Therapeutic Potential 2025 · Genetics

More on Down syndrome and Alzheimer's

• A review that covers this ground Exploring the Pathogenesis of Alzheimer Disease in Basal Forebrain Cholinergic Neurons: Converging Insights From Alternative Hypotheses Frontiers in neuroscience · 2019-05-07 · usefulness score 48/100
• Newest in this subject Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction bioRxiv · 2026-10-30 · Preprint — not yet peer-reviewed · usefulness score 16/100
• Newest in this subject Memory and Plasma pTau217 Refine Prognosis in Down Syndrome Annals of neurology · 2026-10-02 · Peer-reviewed · usefulness score 47/100

See all studies in Down syndrome and Alzheimer's →