Two Important "D" Genes -- DYRK1A and DSCR1

Science is full of long names shortened by using acronyms. Don't let it bother you. Just roll with it. When scientists came up with fun names, like sonic hedgehog (after the video game), they got in trouble because then it becomes a disease of the same name. Ooops! So, for the most part scientist are stuck naming proteins, and other chemicals by their function.

The 2 we are going to look at are DYRK1A and DSCR1.

DYRK1A is a gene on the 21st chromosome It's name is really confusing. It literally stands for.....Dual specificity tyrosine-phosphorylation-regulated kinase 1A. Now you know why everyone just calls it DYRK1A.

The gene DYRK1A gives the instruction for the cell to make an enzyme by the same name, DYRK1A. Just for those who skipped biology class, enzymes are mainly proteins, that speed up certain chemical reactions. Enzymes are used inside of cells to aid in cell growth and reproduction.

An example of enzymes that most people are aware of are digestive enzymes. They speed up the breakdown of our food.

Back to DYRK1A and DSCR1......

DSCR1 is another gene on the 21st chromosome. And it stands for 'Down syndrome critical region 1'. Everyone has this gene. Stanford's DS mice had the symptoms of down syndrome even if this was the only gene that was tripled.

There are a few more letters you have to follow. NFATc. I know, I know.... but this is the key to the problem in this chemical pathway in Down syndrome. NFATc (or Nuclear factor of activated T-cells, cytoplasmic 1) is a protein that is very, very important in neurogenesis (new nerves being created), cell proliferation, cytokinesis (literally means cell movement but is involved in cell division) and cellular differentiation (a cell becomes a certain tissue for example, a nerve cell or a skin cell).

Now let's get to the nuts and bolts of these genes/enzymes and what they do. I found a picture that shows exactly what is going on.

The picture on the left is a picture of a normal functioning cell. There is an {'a'} above it. The picture on the right is of a Down syndrome cell and has a {b} above it.

Notice how calcium comes into the cell at the top and triggers a pathway called Calcineurin (green arrow) and that in turn triggers NFATc which is necessary for cell growth.

In the Down syndrome cell, {b}, there is 1.5 times the amount of the 2 genes discussed above. Remember they are just letters. DSCR1 (pink oval) and DYRK1A (pink oval). The DSCR1 turns down (as in volume) the Calcineurin pathway (red sideways T) and at the same time DYRK1A pulls the NFATc (green oval) out of the nucleus.

The abnormal balance limits cell growth and proliferation. So, these genes are really disrupting new nerve growth, healthy cell production and normal regeneration of cells. What does this mean for Down syndrome? We will delve into the consequences of the imbalance tomorrow.

Early Pharmacotherapy????

An outstanding piece of evidence emerged June of this year. Early treatment of the Down syndrome mouse "restores" cognitive performance. They didn't say "invents" cognitive performance. They say RESTORES. This implies that it is there waiting to be unleashed. And in fact, that is exactly what we observe with the children treated with the CMF protocol. The medicine unveils the awesome person inside.

The medicine used in this study was prozac (fluoxetine generic name). The nerves don't grow or develop properly in the memory area of the brain in Down syndrome. With early treatment with prozac, these DS mice had more normal brain development and had a complete recovery of memory task performance.

All I can say is WOW! We should be dancing on the rooftops and down on our knees thanking God. How easy is this. A known drug with 30 year history and cheap (as low as $3/ month at Walmart).
Watch John (5yo) in action who has been treated with prozac since he was 2 years old:
http://changingmindsfoundation.org/documents/videoblog.html

 Here is an abstract of the study mentioned above:

J Neurosci. 2010 Jun 30;30(26):8769-79.

Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for Down syndrome.
Bianchi P, Ciani E, Guidi S, Trazzi S, Felice D, Grossi G, Fernandez M, Giuliani A, Calzà L, Bartesaghi R.
Department of Human and General Physiology, University of Bologna, I-40126 Bologna, Italy.

Abstract
Down syndrome (DS) is a genetic pathology characterized by intellectual disability and brain hypotrophy. Widespread neurogenesis impairment characterizes the fetal and neonatal DS brain, strongly suggesting that this defect may be a major determinant of mental retardation. Our goal was to establish, in a mouse model for DS, whether early pharmacotherapy improves neurogenesis and cognitive behavior. Neonate Ts65Dn mice were treated from postnatal day (P) 3 to P15 with fluoxetine, an antidepressant that inhibits serotonin (5-HT) reuptake and increases proliferation in the adult Ts65Dn mouse (Clark et al., 2006). On P15, they received a BrdU injection and were killed after either 2 h or 1 month. Results showed that P15 Ts65Dn mice had notably defective proliferation in the hippocampal dentate gyrus, subventricular zone, striatum, and neocortex and that proliferation was completely rescued by fluoxetine. In the hippocampus of untreated P15 Ts65Dn mice, we found normal 5-HT levels but a lower expression of 5-HT1A receptors and brain-derived neurotrophic factor (BDNF). In Ts65Dn mice, fluoxetine treatment restored the expression of 5-HT1A receptors and BDNF. One month after cessation of treatment, there were more surviving cells in the dentate gyrus of Ts65Dn mice, more cells with a neuronal phenotype, more proliferating precursors, and more granule cells. These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS.



PMID: 20592198 [PubMed - indexed for MEDLINE]

Prozac Anyone?

Another study published June 2010 supports the use of Prozac in Down syndrome. Not only does it support the use of Prozac, it indicates Prozac should be started early, probably at birth. Maybe prenatally if you could.
The goal of the study was to see if early pharmacotherapy would improve neurogenesis and cognitive behavior. Guess what? It did.
Neurogenesis is literally what it sounds like. The birth of new neurons or nerves. It is now known that the ability to grow new nerves is a life long affair. At one time, it was believed that higher mammals (humans) did not have the ability to grow new neurons. It has come to light in the research world that we are not above new neurons. In fact, losing the ability to stimulate the growth of new neurons is what leads to depression and other neurodegenerative conditions.
Prozac has been on the market for 30 years. Over 55 million prescriptions have been written. If it had a terrible side effect, we would know. Stomach upset is the most common side effect. I get that from Mexican food.
I'm not making light of using drugs but my point is that weighing the options of degeneration versus regeneration, I'll take the regeneration, thank you.
The study looked at memory and learning in the Down syndrome mouse model. The DS mice did just as well as the typical mice in memory tests.

"These animals were tested for contextual fear conditioning, a hippocampus-dependent memory task, and exhibited a complete recovery of memory performance. Results show that early pharmacotherapy with a drug usable by humans can correct neurogenesis and behavioral impairment in a model for DS."

The abstract and full study is available online "Early Pharmacotherapy Restores Neurogenesis and Cognitive Performance in the Ts65Dn Mouse Model for Down Syndrome"
The thing we should be jumping up and down about is RESTORES COGNITIVE PERFORMANCE!!!!

Timing Times Two

At the first annual CMF conference we discussed Prozac. This seems to be the scariest drug for most parents. Today I wanted to discuss the timing of research, and Prozac is an excellent example.

In April of 2006 a study was published "Fluoxetine Rescues Deficient Neurogenesis in Hippocampus of the Ts65Dn Mouse Model for Down Syndrome". The study gave fluoxetine (which is generic Prozac) to the DS mouse and then examined the memory and learning area of the brain (which is called the hippocampus) 3 weeks later. Within 3 weeks, the brain had formed twice the number of nerves than before. Notice the title of the study, "...Rescues Deficient Neurogenesis...". This tells us that we know people with Down syndrome are naturally deficient at growing new neurons on their own, without some kind of help.

Back to timing. A second study, that looked at learning and memory in the Down syndrome mouse, concluded that after being treated with Prozac the mice had a "complete recovery of memory performance". Aren't these the kind of conclusions we want? Do you know when that study was published?

June of 2010

It took 4 years from one study to the next! Wow !!

Do we believe these studies and move forward and treat with a drug that has been on the market for 30 years, or do we wait 4 more years?