Can't get Away From DYRK1A

I found this picture. Wow! Look at how many things are affected by DYRK1A.
I recommend reading the journal article where I got this. You can download the picture from the journal into a power point slide and then it is clear. Link

We talked about Tau, App and NFATc but did not even define the rest.
It is amazing how many items 1 gene can affect. Unbelievable!!

EGCG, DYRK and Folate ie. green tea, increased gene and a B vitamin... Kinda.....

I took a minibreak from DYRK1A etc. But it is time to think about it again. Andi commented below about green tea and folate and I was getting to that but it involves another pathway.........Methylation.

Methylation is a very important basic process in the body. In the late 1990's Neal and his buddies with DS sent their blood to a researcher named Dr. Jill James. She discovered that the methylation pathway is disturbed in DS (and in us Moms) because some of the enzymes in the pathway are overexpressed. It is easier to look at a diagram than just to write about it.

Here is an overview of the Methylation Pathway. We are going to talk about the 2 things in red. In the middle of the diagram is CBS (cystathione beta synthase). This enzyme is triplicated on the 21st chromosome which presumably pulls that pathway down.
The second scratchy red is 5-CH3 THF - which is methyl tetrahyrdrofolate.
Have you have heard of folic acid? It is added to every cereal. "Fortified with Folic Acid".

There is a very knowledgable website called Super Down Syndrome that has a terrific explanation about many topics. But one is an explanation about folic acid versus folinic acid.
"...medical professionals still haven’t figured out that folic acid is not the same as the naturally occurring vitamin folate.

Folic acid is a single type of molecule, crystallized in 1943 by a scientist working for the patent medicine company Lederle Laboratories, then a subsidiary of American Cyanamid Corporation. Folic acid is the fully oxidized form of naturally occurring folates, which are found in leafy and green vegetables......

Folate was originally isolated from brewer’s yeast and spinach in the 1930s. Once isolated and exposed to air it becomes unstable and breaks down, and is generally no longer useful in nutrition. But a small amount of natural folate can be transformed by oxidation (a natural process) into folic acid, a much more stable form with a very long shelf life.
While human and animal cells cannot use the folic acid molecule itself in their normal metabolic processes, human cells (principally the liver) can transform folic acid back into many of its metabolically useful folate forms. That’s why folic acid—despite not being found in food—can do so much nutritional good, the best-known example being the prevention of birth defects including spina bifida, cleft lip, and cleft palate."
But what if your population cannot utilize folic acid? It is necessary to supplement with the more active form folinic acid which translates to 5-methyl tetrahydrofolate. Sound familiar? It is the folate in the cycle.

 Neal and I for that matter supplement with Folinic acid.

OK here comes the complication from green tea extract and folates. Green tea reduces an enzyme (DHFR) [orange] that converts folic acid tetrahydrofolate in one direction - here is another diagram:

But I now think that the DYRK1A is sufficiently dangerous that it is worth turning it down and then supplementing with a good form of folate. It is important to add B12 (green) as well. You didn't think this was going to be easy did you? The medical profession has thrown their collective hands up for years saying Down syndrome is too complicated to treat. They continue to say there are too many things wrong. True enough. But I think we can unpeel this syndrome like an onion. Don't get discouraged that there is another layer. Be prepared there are more layers to come.
We will look more closely at these pathways because there are more complications than we have discussed today.

Review Again and Again and Again

Whew!! These blogs have been a lot of science. If you are still with me, let's review.
3 Players:
These genes are at a triple dose in Down syndrome:

1. DYRK1A
2. RCAN or (DSCR1)
3. APP

DYRK1A is triplicated (3X) in Down Syndrome and is involved in cell growth and development.

• decrease brain volume (slows cell growth and development)
• decreases synaptic plasticity [decreases BDNF (Brain Derived Neurotrophic Factor)- like brain food]
• increases the production of the toxic amyloid beta plaque
• hyperphosphoralates tau protein which is a structural protein inside the nerves. The tau protein falls off the internal structure leading to collapse of the nerve

RCAN or (DSCR1)

• decreases cell growth and therefore brain volume
• the DSCR stands for Down Syndrome Critical Region. It has since been renamed to RCAN

APP stands for Amyloid Precursor Protein

• 3 enzymes cut this protein in different spots
•  the DYRK1A changes the APP and sets it up to be cut in a toxic manner creating the poisonous amyloid beta plaque.
• The amyloid beta plaque is hallmark of Alzheimer's and Down syndrome brain pathology
• in a mouse model, 3 times APP alone does not show the same pathological changes seen in Down syndrome
• in a mouse model, 3 times APP and 3 times DYRK1A does resemble the brain changes seen in Down syndrome. Also, these mice have similar learning deficiencies seen in Down syndrome.

What can we do to help turn down these genes? Well obviously we need to rebalance the system if we can.

One thing came up over and over in the journal articles. GREEN TEA EXTRACT

Green Tea Extract decreases the expression of the DYRK1A gene.

So, if DYRK1A was expressed at a more normal level, the person with Down syndrome should be able to grow nerve cells and therefore normalize brain volume. Learning and memory should increase with more synaptic plasticity. Forming less amyloid beta plaques should at least delay the onset of toxic plaque build up in the brain. And, structurally, the tau protein should stay more normal therefore, less nerve cells will collapse.

Another journal article, found that ANTIDEPRESSANTS decrease the expression of the RCAN gene. There were some contradictory studies on this point but ANTIDEPRESSANTS also are known to increase BDNF which is probably a good thing in Down syndrome.

Thanks for the comments on facebook. I know this is tough stuff but you don't have to know every detail. You need to understand the overall pathology that is an ongoing problem in Down syndrome. 'WE CAN' help our loved ones with Down syndrome. It is like an onion one layer at a time.

Tau Protein and DYRK1A and Nerves

Let's continue to breakdown the details of the biological happenings and then we will put the information back together into a 'big' picture overview.
The tau protein is an important structural component inside the nerve. The following is an excellent explanation:
"Tau is abundant in neurons and binds to microtubulin where it has a pivotal role in microtubule growth and stability. And if it affects microtubule growth, then it affects not only cellular architecture but also cellular trafficking, since cells use microtubules as motorways to deliver nutrients and other molecules to different destinations. Without the assistance of tau, neurons are then neither able to elongate, nor to regenerate. In AD [Alzheimer's Disease], tau structure is modified via hyperphosphorylation and instead of assisting microtubulin, it creates tangled clumps of fibres in the neurone’s cytosol." (1)

The tau protein is critical to the structure of the nerve and the transportation system inside the nerve. When the tau protein is chemically altered, it loses its ability to connect with the nerve structure and then disrupts it. It is like collapsing bridges in a highway system. There is no way to cross the river and soon the nerve cell dies and disappears.
How is tau protein changed?
The DYRK1A gene instructs the cell to 'phosphoralate' the tau protein

   Phosphorylation is the addition of a phosphate (PO4)  to a protein or other organic molecule.

Phosphorylation activates or deactivates many protein enzymes.

  The best theory is that having 1.5 times of the DYRK1A gene leads to' hyperphosphalation'. This means that phosphate groups (PO4) are added to the tau protein in an excessive manner.  The result of this chemical change is that the tau protein falls off of the microtubules inside the nerve, clumps together and the nerve soon collapses.

Here is a video of this process. There is no sound but the animation is very good.

Video of tau protein in AD or DS

Next blog we will put the different pieces together.


(1) http://expasy.org/spotlight/back_issues/118/

Could the DYRK1A gene increase Amyloid Plaques?

In the last post, we talked about the amyloid plaque and how it gunks up the works (ie. brain). Just to review, Down syndrome have 3 copies of the APP gene, which stands for amyloid precursor protein. But their is a twist to the story, "over-expression of APP alone in mice does not cause the AD-like (Alzheimer Disease - like) [endosome] pathology observed in DS patients."  So just having 3 copies of the APP gene does not create the biological disease state that is seen in Down syndrome, mice and people.

So, the next question is what else contributes to the formation of amyloid plaques and therefore, a disease state?

We are back to our friendly DYRK1A gene. Having 3 copies of DYRK1A plus 3 copies of APP creates the perfect storm that does result in the pathology seen in patients with Down syndrome. Another link in the chain.

{We need a big white board to keep track of all the connections.}

OK back to the science:

Let's look at how DYRK1A affects APP.

"DYRK1A and APP give rise to AD pathology in DS brains through

DYRK1A-mediated phosphorylation of APP." (1)

Phosphorylation means to activate or deactivate protein enzymes

"The over-expression of DYRK1A in DS brains may accelerate the development of

AD pathogenesis through phosphorylation of the Thr668 residue of APP, a

modification that may be necessary for the APP cleavage events that give rise to Aβ (amyloid beta plaque)."(1)
Let's review :

• The brain chemistry in Down syndrome is producing the toxic amyloid plaques at a higher rate than normal.
• A mouse model with only triple APP does not show the same pathology as seen in Down syndrome.
• A mouse model with only triple DYRK1A does show learning and memory deficiencies similar to Down syndrome.
• A mouse model with a triple APP and DYRK1A show the same pathology seen in human Down syndrome brains.

At the end of the study cited above, they say, "therapeutics that inhibit DYRK1A expression and/or kinase activity might suppress the early-onset of AD and mental retardation in DS patients." (1)
A few potent DYRK1A inhibitors have been described but the one that keeps popping up in these journal articles is epigallocatechin 3-gallate (EGCG), in other words, green tea extract.
We will continue this scientific avenue looking at tau protein (strucural component inside nerves) next. Review the video in previous post.

Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease  (1)

What do we do next?

The one thing I have found that turns down the DYRK1A is green tea extract. It is widely available and fairly inexpensive. What dose do we need? I don't know. I started giving Neal 1500mg per day. Is that too much or is it too little?????
This is where basic research comes in to answer these questions.
A friend sent an interesting study that said antidepressants turned down the DSCR (or RCAN1) gene expression. http://www.ncbi.nlm.nih.gov/pubmed/17207580
So the 2 things we have at this moment are Green Tea Extract and Antidepressants.

Another Piece of the Complicated Puzzle

As we have been discussing, in the case of Down syndrome, the balance of DYRK1A gene and DSCR1 gene is off. They are at 1.5 times the normal amount. Another aspect of this imbalance that may make it a really big deal is that one of the major things this affects is the immune system.

Immunosuppressant drugs are used to turn down the immune system when, for example, a person has an organ transplant. The drugs help to turn down the immune system so that the organ is not rejected. The way immunosuppressant drugs work is exactly like having too much DYRK1A and DSCR1. The person with Down syndrome is in a constant state of suppressing their immune system.

Synaptic Plasticity and Down syndrome

As promised, SYNAPTIC PLASTICITY. Ooooh! But seriously, it's very, very important.
Synaptic Plasticity literally means the ability of the connection between two nerves to strengthen when learning something or weaken when forgetting something. I know, that may sound funny but it is very important to be able to forget as well as remember.
The end of the nerve has a bouton which is like a little pod. In that pod are little containers of chemicals called neurotransmittors. When an electical charge comes down the nerve, the containers of neurotransmittors are moved to the edge and they release their chemicals into the space between the two nerves. At this point, the chemicals attach themselves to receptors on the next nerve and open a tube that allows calcium, for example to rush into the nerve changing the charge sending the electrical charge down the second nerve. In other words, the way a nerve works is first there is an electrical charge which turns into a chemical change and back into electrical charge in the connecting second nerve.
Here are a  few pictures:

Here is a short animation of the synapse and how it works:

Now, back to synaptic plasticity and Down syndrome. The ability of the synapse to adapt and learn is dependent on BDNF (Brain Derived Neurotophic Factor). Oh no, more letters!!

This chemical (BDNF) is a necessary part of learning. When the amount of DYRK1A was decreased, BDNF increased and so did synaptic plasticity. So having 1.5 times of DYRK1A as much as normal, decreases the ability of the synapse to change and therefore, learn.

How DYRK1A Affects the Brain and Memory

The last blog involved the specific way DYRK1A worked. Now let's look at how it affects the brain and memory. Here are the 3 big ways that research has discovered to date. Remember, researchers keep adding details every year.

The first way DYRK1A affects the brain is from the beginning it is involved in the development of the brain. Specifically, it affects the normal brain volume.

The second affect is disrupting synaptic plasticity. Synaptic plasticity is the ability of the connection, or synapse, between two nerves to change. This connection strengthens and weakens as things are learned and forgotten.

The third big category that DYRK1A affects is memory consolidation. Memory consolidation is a process that stabilizes a memory trace after the initial acquisition.
 
This gene is turning out to be super-duper important! Let's explore the first piece of brain development.

"DYRK1A is a major player in both cell cycle regulation and synaptic plasticity. DYRK1A levels in the brains of DS subjects with free trisomy were found approximately 1.5-fold higher than those in normal subjects indicating that this protein is overproduced in a gene dosage-dependent manner in Down syndrome."   Guedj F et al.

Since it is involved in cell growth and reproduction, it is essential during development. In other words, having the correct dose of DYRK1A is an integral part of brain growth. At 1.5 times the amount, cell growth is disrupted, thereby, leading to low brain volume.

Is there anything we can do about the DYRK1A? Lucky for us, there are many studies looking at this problem.

There is one study published in 2009 called 'Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.

I love the word 'rescue.'

PLoS One. 2009;4(2):e4606. Epub 2009 Feb 26.

'Green tea polyphenols rescue of brain defects induced by overexpression of DYRK1A.'

Guedj F, Sébrié C, Rivals I, Ledru A, Paly E, Bizot JC, Smith D, Rubin E, Gillet B, Arbones M, Delabar JM.

Functional and Adaptive Biology, Université Paris Diderot-Paris7 and CNRS, Paris, France.

The complete study is free online. Here is the link:
 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2645681/?tool=pubmed

But in essence they reversed or as they put it rescued, brain volume, learning deficits and synaptic plasticity feeding the transgenic mice green tea polyphenols. Transgenic mice have been genetically altered from the wild type mice or normal mouse.

"We investigated the possibility of correcting these phenotypes through modulation of DYRK1A activity. EGCG can cross the blood-brain barrier and the placental barrier. EGCG is the major catechin in green tea leaves (40 to 50% of the total catechins amount). Indeed, feeding a green tea drink to mice (usually drinking 3–5 ml/day) is equivalent to administering 0.6 mg/day pure EGCG."

Green tea reduces the activity of DYRK1A. In essence returning the gene expression to a more normal amount.

They fed mice a green tea drink from gestation (started during initial mating period) to adulthood and saw positive results. Using MRI technology the researchers measured brain volume.

To test learning deficits, researchers use what is called a novel object recognition test. This test is where the mice are trained with 2 objects and then one of the objects is changed to a new object. Mice should spend most of their time checking out the new object and less time with the familiar object.

The results were significant. The transgenic mice fed the green tea had no learning deficit while the transgenic mice fed only water had close to zero memory capabilities.

Tomorrow........the burning question...what is synaptic plasticity? And why is it important?