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.
Summary
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.
References
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