Neurology and DYRK1A gene in Trisomy 21

Neurology and DYRK1A gene in Trisomy 21

In this article I am beginning to explore the key genes which affect cognitive function in Trisomy 21. There are so many genes at play and as discussed in my previous article – Trisomy 21 a Deeper Look  they inter relate with each other and with genes on other chromosomes, so it seems unlikely that focusing on one or two one or two genes will actually have an impact.  However surprisingly there are some key genes which when inhibited do have a profound effect on cognitive function (12-14).

It is always important to remember that T21 is a neurodegenerative disease. The effects it has on the brain worsen with age (10).

There have been some promising studies done on young adults with T21, where cognitive improvements occurred (7, 11).

Trisomy 21 Neurology – What’s happening in the brain?

How is the brain of someone with T21 different to a typical brain?

In general people with T21 have a smaller brain (10) – Brain hypotrophy. This is particularly prominent in the;

  • Cerebellum – coordination, balance, muscle activity
  • Frontal cortex – Thinking, planning, decision making
  • Hippocampus – Learning, memory

This hypotrophy is believed to be due to impairments in brain neurogenesis – growth and development of nervous tissue, starting from the begining of brain development – embryonic/fetal life stages (11). This hypotrophy may be in part due to a reduced amount of neurons (nervous system cells) of neurons and an increased amount of astrocytes (9).

  • Neurons are essential for sensory transmission, sending and receiving information,
  • Astrocytes are an essential component of the blood brain barrier.

This suggests the cell division and differentiation process is flawed, producing too many astrocytes and not enough neurons.  Excess astrocyte production is linked to excess amyloid beta (AB) plaques – It is thought that AB plaques trigger neurofibrillary tangles (NFT), neuronal cell death, neuro-inflammation and gliosis and, ultimately, cognitive impairment (21). AB plaques and NFT’s are components of Alzheimers disease (21).

As neurons are essential for sending and receiving sensory information, under production will have a big impact on neurological processes – learning, development, movement, memory etc.

The neurons which are produced have an excitation/inhibition imbalance and decreased neuronal firing rate – so information is travelling more slowly and adaptation is impaired (22).

The genes DYRK1A and DSCR1/RCAN1, contribute to these features of a T21 brain (9)

DYRK1A – Dual-specificity tyrosine phosphorylation-regulated kinase 1A

DYRK1A is one of the genes over expressed on the 21st chromosome in individuals with T21. DYRK1A is strongly expressed in the cerebral cortex a part of the brain responsible for conscious thought. The functions of DYRK1A include;

  • Cell differentiation (1) – What cells will develop into eg. neuron or astrocyte
  • Cell cycle regulation (1) – Division and replication of the cell
  • Cell proliferation and apoptosis (1) – Cell growth and death
  • Synaptic plasticity (22) – Synapses are the junctions between neurons that allow them to communicate, and plasticity is the ability of these junctions to change and adapt.

DYRK1A Over Expression is suspected to be linked to;

  • DS symptoms such as cognitive impairment and reduced brain size (2-3).
  • One of the reasons for the early onset of Alzheimers Disease-like neurodegeneration in DS individuals (3-5, 22).
  • Suppressed neuron production and over production of astrocytes (9)
  • Decreased bone mineralization, bone growth and bone maintenance (6).
  • Decreased cortical excitability with decreased firing rate of cortical neurons (22).
  • Reduced vesicular GABA transporter (VGAT) punctae on parvalbumin-expressing interneurons that suggest impaired modulation of inhibition (22)
  • Alterations in synaptic plasticity pathways, particularly expression changes in GABAergic and glutaminergic related proteins (23)

Physiological features of cortical neurons and their synapses play a role in shaping the activation of the cortical network, with the balance between excitation and inhibition being a critical factor.  DYRK1A overexpression leads to defective cortical pyramidal cell morphology

Several authors have reported impairments in prefrontal cortex (PFC) in Down syndrome that present a reduction in volume (24, 25, 26) and a decrease in intrahemispheric and interhemispheric connectivity (27). As a consequence of such impairments, PFC executive function and inhibitory behavioral control, which are the major contributing factors to intellectual disability, are compromised in Down syndrome individuals (27, 28, 29,  de Sola et al., 2015).

Inhibitors of DYRK1A

The most promising substance for inhibition of DYRK1A has been found to be the Green tea flavonol – epigallocatechin-gallate (EGCG). Numerous studies on T21 mouse models,  and promising studies on young adults with T21 have found that consumption of EGCG suppresses DYRK1A activity and thus;

  • reverses cognitive deficits in young adults (7)
  • restores hippocampal neurogenesis (15)
  • rescues defective long-term potentiation in the prefrontal cortex (8)
  • corrects brain morphogenesis alterations (16)
  • Restores hippocampal neurogenesis (9)
  • Rescues defective long-term potentiation in the prefrontal cortex(17).
  • Restores components of GABAergic and glutamatergic pathways in the cortex and hippocampus, and improves behavioral deficits (18).
  • Rescues mitochondrial function and promotes mitochondrial biogenesis (19) study initially done in mice and then with a 10 year old boy with DS.
  • Improves bone mineralisation and bone density (6)
  • In a study, young adults with DS (29 subjects) aged 14–29 years were treated with either green tea extracts in capsule form EGCG (mean EGCG oral dose of 9 mg/kg/day) or a placebo for three months (7). The effects of treatment on indices of neuropsychological performance were examined after 3 months of treatment and 3 months after treatment discontinuation. After 3 months of treatment, EGCG-treated individuals showed a significantly higher percentage of correct answers in visual memory recognition compared with those who had been given the placebo. Three months after treatment discontinuation this effect declined, and treated subjects had a performance that returned to baseline measures.
  • In a subsequent study, (11) with 84 adults, examined the effect of cognitive training alone or cognitive training plus green tea extract for a 12 month period.  The supplement was in capsule form containing 45% EGCG.  Subjects were tested with a battery of neuropsychological tests periodically during treatment, at 12 months (i.e., immediately following treatment cessation) and at 6 months after treatment discontinuation. At 12 months, there were significant differences between the two groups in two of the 15 tests developed for testing cognitive performance and in one of the nine adaptive skills. Subjects that received cognitive training plus EGCG had a better performance in these three tests in comparison with the group that received cognitive training only. Some of these effects persisted in the cognitive training plus EGCG group.

It is worth noting that EGCG can cross the blood-brain and placental barriers (20), pregnant mothers of a baby with DS in utero could supplement.


The use of EGCG as an inhibitor of the DYRK1A gene,  leading to overall improvement in brain morphology, neuron numbers and function, synapse plasticity and balanced inhibition and excitation within the brain is incredibly promising.


1. Fabbro, D. 25 years of small molecular weight kinase inhibitors: Potentials and limitations. Mol. Pharmacol. 2015, 87, 766–775. [CrossRef] [PubMed]

2. Park, J.; Song, W.-J.; Chung, K.C. Function and regulation of Dyrk1A: Towards understanding Down syndrome. Cell. Mol. Life Sci. 2009, 66, 3235–3240. [CrossRef] [PubMed]

3. Yabut, O.; Domogauer, J.; D’Arcangelo, G. Dyrk1A overexpression inhibits proliferation and induces premature neuronal differentiation of neural progenitor cells. J. Neurosci. 2010, 30, 4004–4014. [CrossRef] [PubMed]

4. Tejedor, F.J.; Hämmerle, B. MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J. 2011, 278, 223–235. [CrossRef] [PubMed]

5.  Abbassi, R.; Johns, T.G.; Kassiou, M.; Munoz, L. DYRK1A in neurodegeneration and cancer: Molecular basis and clinical implications. Pharmacol. Ther. 2015, 151, 87–98. [CrossRef] [PubMed]

6. Joshua D. Blazek, Irushi Abeysekera, Jiliang Li, Randall J. Roper; Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a, Human Molecular Genetics, Volume 24, Issue 20, 15 October 2015, Pages 5687–5696,

7. De la Torre, R., De Sola, S., Pons, M., Duchon, A., de Lagran, M. M., Farré, M., Fitó, M., Benejam, B., Langohr, K., Rodriguez, J., Pujadas, M., Bizot, J. C., Cuenca, A., Janel, N., Catuara, S., Covas, M. I., Blehaut, H., Herault, Y., Delabar, J. M. and Dierssen, M. (2014), Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans. Mol. Nutr. Food Res., 58: 278–288.

8. Thomazeau A, Lassalle O, Iafrati J, Souchet B, Guedj F, Janel N, Chavis P, Delabar J, Manzoni OJ.. Prefrontal deficits in a murine model overexpressing the Down syndrome candidate gene dyrk1a. J Neurosci 2014; 34:1138-47; PMID:24453307; [PMC free article] [PubMed] [Cross Ref

9. Kurabayashi N1, Sanada K1. Molecular Mechanism Underlying Abnormal Differentiation of Neural Progenitor Cells in the Developing Down Syndrome Brain. Vol 137 (2017) Issue 7 p. 795-800 (article in Japanese).

10. Stagni F, Giacomini A, Emili M, Guidi S, Ciani E, Bartesaghi R. Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome? Neurogenesis. 2017;4(1):e1270383. doi:10.1080/23262133.2016.1270383.

11. De la Torre R, de Sola S, Hernandez G, Farre M, Pujol J, Rodriguez J, Espadaler JM, Langohr K, Cuenca-Royo A, Principe A, et al. Safety and efficacy of cognitive training plus epigallocatechin-3 gallate in young adults with Down’s syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet Neurol 2016; 15:801-10; PMID:27302362; [PubMed] [Cross Ref]

12. Bartesaghi R, Guidi S, Ciani E.. Is it possible to improve neurodevelopmental abnormalities in Down syndrome? Rev Neurosci 2011; 22:419-55; PMID:21819263; [PubMed] [Cross Ref]

13. Costa AC, Scott-McKean JJ.. Prospects for improving brain function in individuals with Down syndrome. CNS Drugs 2013; 27:679-702; PMID:23821040; [PubMed] [Cross Ref]

14. Gardiner KJ. Pharmacological approaches to improving cognitive function in Down syndrome: current status and considerations. Drug Des Devel Ther 2015; 9:103-25; PMID:25552901 [PMC free article] [PubMed]

15. Pons-Espinal M, Martinez de Lagran M, Dierssen M.. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1ANeurobiol Dis 2013; 60:18-31; PMID:23969234;  [PubMed] [Cross Ref]
16. Guedj F, Sebrie C, Rivals I, Ledru A, Paly E, Bizot JC, Smith D, Rubin E, Gillet B, Arbones M, Delabar JM.. Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A. PLoS One 2009; 4:e4606; PMID:19242551; [PMC free article] [PubMed] [Cross Ref]
17. Thomazeau A, Lassalle O, Iafrati J, Souchet B, Guedj F, Janel N, Chavis P, Delabar J, Manzoni OJ..     Prefrontal deficits in a murine model overexpressing the Down syndrome candidate gene dyrk1a. J Neurosci 2014; 34:1138-47; PMID:24453307; [PMC free article] [PubMed] [Cross Ref
18. Souchet B, Guedj F, Penke-Verdier Z, Daubigney F, Duchon A, Herault Y, Bizot JC, Janel N, Creau N, Delatour B, Delabar JM.. Pharmacological correction of excitation/inhibition imbalance in Down syndrome mouse models. Front Behav Neurosci 2015; 9:267; PMID 26539088; [PMC free article] [PubMed] [Cross Ref]
19. Valenti D, De Rasmo D, Signorile A, Rossi L, de Bari L, Scala I, Granese B, Papa S, Vacca RA.. Epigallocatechin-3 gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down’s syndrome. Biochim Biophys Acta 2013; 1832:542-52; PMID:23291000; [PubMed] [Cross Ref]
20. Lin LC, Wang MN, Tseng TY, Sung JS, Tsai TH.. Pharmacokinetics of (-)-epigallocatechin-3 gallate in conscious and freely moving rats and its brain regional distribution. J Agric Food Chem 2007; 55:1517-24; PMID:17256961; [PubMed] [Cross Ref
21. Frost GR, Li Y-M. The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biology. 2017;7(12):170228. doi:10.1098/rsob.170228.
22.Marcel Ruiz-MejiasMaria Martinez de LagranMaurizio MattiaPatricia Castano-PratLorena Perez-MendezLaura Ciria SuarezThomas GenerBelen SancristobalJordi García-OjalvoAgnès GruartJosé M. Delgado-GarcíaMaria V. Sanchez-VivesMara DierssenOverexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex 
23. Souchet, B., Guedj, F., Sahún, I., Duchon, A., Daubigney, F., Badel, A., … Delabar, J. M. (2014). Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. Neurobiology of Disease, 69, 65–75.
24. Jernigan TLBellugi USowell EDoherty SHesselink JR (1993Cerebral morphologic distinctions between Williams and Down syndromesArch Neurol 50:186 191,doi:10.1001/archneur.1993.00540020062019pmid:8431138.
25.  Raz NTorres IJBriggs SDSpencer WDThornton AELoken WJGunning FM,McQuain JDDriesen NRAcker JD (1995Selective neuroanatomic abnormalities in Down’s syndrome and their cognitive correlates: evidence from MRI morphometry.Neurology 45:356366doi:10.1212/WNL.45.2.356pmid:7854539.
26. Wisniewski KE (1990Down syndrome children often have brain with maturation delay, retardation of growth, and cortical dysgenesisAm J Med Genet Suppl 7:274281,pmid:2149962PubMedGoogle Scholar
27. Pujol Jdel Hoyo LBlanco-Hinojo Lde Sola SMacià DMartínez-Vilavella GAmorMDeus JRodríguez JFarré MDierssen Mde la Torre R
28. Rowe JLavender ATurk (2006Cognitive executive function in Down’s syndrome.Br J Clin Psychol 45:517doi:10.1348/014466505X29594pmid:16480563.
29. Ball SLHolland AJWatson PCHuppert FA (2010Theoretical exploration of the neural bases of behavioural disinhibition, apathy and executive dysfunction in preclinical Alzheimer’s disease in people with Down’s syndrome: potential involvement of multiple frontal-subcortical neuronal circuitsJ Intellect Disabil Res54:320336doi:10.1111/j.1365-2788.2010.01261.xpmid:20202073CrossRefPubMedGoogle Scholar
30. de Sola Sde la Torre RSánchez-Benavides GBenejam BCuenca-Royo ADel Hoyo LRodríguez JCatuara-Solarz SSanchez-Gutierrez JDueñas-Espin I,Hernandez GPeña,Casanova JLangohr KVidela SBlehaut HFarre MDierssenMGroup TS (2015A new cognitive evaluation battery for Down syndrome and its relevance for clinical trialsFront Psychol 6:708pmid:26089807.