Most citations used are taken from the NLM database and are in the public domain.

OVER EXPRESSED GENES, SOD1, RCAN1 and MICRORNA-155

SOD1:
Let’s continue looking at over expressed genes in DS and how TNI can manage them. We will be looking at substances that do far more to benefit DS than inhibiting or regulating the genes we will be discussing. We will briefly discuss those benefits later.

SOD1: Presently there is no safe way to down regulate SOD1. Superoxide Dismutase, over expressed in Down syndrome, is an enzyme. To understand an enzyme think of this one as shaped like a pie with a wedge removed. All enzymes are shaped to correspond to their unique substrate. In this case that substrate is called superoxide. Picture it as shaped like the missing piece of the pie. When the missing wedge joins with the pie a chemical reaction occurs.

STOP HERE AND WATCH THIS VIDEO

How Enzymes Work

https://m.youtube.com/watch?v=yk14dOOvwMk

SOD1 catalizes the dismutation (or partitioning) of the superoxide (O2−) radical into either ordinary molecular oxygen (O2) or hydrogen peroxide (H2O2). Superoxide is produced as a by-product of oxygen metabolism and, if not regulated, causes many types of cell damage. Hydrogen peroxide is also damaging and is degraded by other enzymes such as catalase. In DS it is this next step, the degradation of hydrogen peroxide that produces excess oxidative stress. Two enzymes, Glutathione Peroxidase and Catalase step in here to change hydrogen peroxide to necessary water and oxygen. But Catalase and Glutathione Peroxidase are NOT over expressed in DS. The result is free hydrogen peroxide that ultimately becomes the most dangerous free radical known in science, the hydroxyl free radical. It is so destructive that it not only damages the cell and its organelles, it damages the DNA within the nucleus.

STOP HERE AND WATCH THIS VIDEO – WHAT IS A FREE RADICAL?

Oxygen free radicals & cellular injury – causes, symptoms & pathology and How Antioxidants Work

https://m.youtube.com/watch?v=lG3OOXIXvxw

Since we cannot safely down regulate SOD1 how do we manage this? The answer is three fold, 1) Nutrivene is designed to upregulate the production of both Catalase and Glutathione Peroxidase. This balancing of this antioxidant triad results in far better management of hydrogen peroxide. Our efforts were proven successful in the study of Nutrivene at the University of Cairo, Egypt in 2001

PLEASE READ

http://trisomy21research.org/2017/09/19/the-miguid-study-on-nutrivene/

The findings of this study prompted the reformulation and improvement of the formula for even better results.

2) Exogenous antioxidants. Nutrivene contains antioxidants that protect cells from damage from free radicals.

3) Superoxide scavengers. For our purposes, we utilize PQQ which is not only an excellent Superoxide scavenger but it triggers the genesis of new, healthy mitochondria and supresses the toxin, Peroxynitrite. This is extremely important as Peroxynitrite combines with TAU and amyloid Beta proteins in the creation of plaque. Thus we remove yet one more piece of the Alzheimer’s disease puzzle. We remove those things that in combination bond to form this dangerous substance which destroys the brain.

PLEASE READ

https://www.ncbi.nlm.nih.gov/pubmed/12383230

Moving forward, let’s look at RCAN1.

The protein encoded by this gene interacts with calcineurin A and inhibits calcineurin-dependent signaling pathways, possibly affecting central nervous system development. This gene is located in the minimal candidate region for the Down syndrome phenotype, and is overexpressed in the brain of Down syndrome fetuses. Chronic overexpression of this gene may lead to neurofibrillary tangles such as those associated with Alzheimer disease. Alternative splicing results in multiple transcript variants.

PLEASE READ – HOW RCAN1 OVER EXPRESSION EFFECTS DS

https://www.ncbi.nlm.nih.gov/pubmed/22511596

https://www.ncbi.nlm.nih.gov/pubmed/23644448

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682116/

https://www.hindawi.com/journals/omcl/2014/520316/

Obviously m we cannot allow this protein to remain elevated. PQQ particularly corrects this problem by activating CREB which, in turn, regulates RCAN1 but the best results are obtained by the use of Lycopene which actually prevents oxidative stress associated with the over expression of RCAN1.

PLEASE READ THE INHIBITORY EFFECTS OF LYCOPENE ON CELL DAMAGE CAUSED BY THE OVER EXPRESSION OF OF RCAN1

https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201600530

https://www.researchgate.net/publication/319312739_Inhibitory_Effect_of_Lycopene_on_Amyloid-b-Induced_Apoptosis_in_Neuronal_Cells

MicroRNA-155

What is a MicroRNA?

A microRNA (abbreviated miRNA) is a small non-coding RNA molecule (containing about 22 nucleotides) found in plants, animals and some viruses, that functions in RNA silencing and post-transcriptional regulation of gene expression. In Down Syndrome there are at least five over expressed mRNAs.

MicroRNA-155 is a very serious problem in DS as it is involved in numerous diseases and abnormalities found in the DS population such as autoimmune diseases, Leaky blood brain barrier, neuro inflammation, skin disorders, and the under expression of SNX27 and MECP2, both critical proteins normally regulated by mRNA 155. These issues and numerous others caused by the over expression of this mRNA greatly diminishes the health and cognitive function of our children.

PLEASE READ MicroRNA-155 RELATED DISEASES AND DISORDERS

Neuro Inflammation and Leaky BBB

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378916/
Autoimmune diseases

https://www.ncbi.nlm.nih.gov/pubmed/21703910

The Role of mRNAs in Skin Diseases/disorders

https://onlinelibrary.wiley.com/doi/pdf/10.1111/sji.12261

SNX27 and Down Syndrome

Recently, researchers Xu and colleagues started out working with mice that lack one copy of the snx27 gene. They noticed that the mice were mostly normal, but showed some significant defects in learning and memory. So the team dug deeper to determine why SNX27 would have that effect. They found that SNX27 helps keep glutamate receptors on the cell surface in neurons. Neurons need glutamate receptors in order to function correctly. With less SNX27, these mice had fewer active glutamate receptors and thus impaired learning and memory.

SNX27 levels are low in Down syndrome
Then the team got thinking about Down syndrome. The SNX27-deficient mice shared some characteristics with Down syndrome, so they took a look at human brains with the condition. This confirmed the clinical significance of their laboratory findings—humans with Down syndrome have significantly lower levels of SNX27.
Next, Xu and colleagues wondered how Down syndrome and low SNX27 are connected—could the extra chromosome 21 encode something that affects SNX27 levels? They suspected microRNAs, small pieces of genetic material that don’t code for protein, but when elevated can cause the decrease in SNX27.

Xu and his team concluded that, due to the extra chromosome 21 copy, the brains of people with Down syndrome produce extra miR-155, which by indirect means decreases SNX27 levels, in turn decreasing surface glutamate receptors. Through this mechanism, learning, memory, and behavior are impaired.

Restoring SNX27 function rescues Down syndrome mice

If people with Down syndrome simply have too much miR-155 or not enough SNX27, could that be fixed? The team explored this possibility. They used a noninfectious virus as a delivery vehicle to introduce new human SNX27 in the brains of Down syndrome mice.

“Everything goes back to normal after SNX27 treatment. It’s amazing—first we see the glutamate receptors come back, then memory deficit is repaired in our Down syndrome mice,” said Xin Wang, a graduate student in Xu’s lab and first author of the study. “Gene therapy of this sort hasn’t really panned out in humans, however. So we’re now screening small molecules to look for some that might increase SNX27 production or function in the brain.”

But how can we restore SNX27? By down regulating MicroRNA-155. This, we accomplished with Resveratrol.

Resveratrol Down Regulates MicroRNA-155

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4647642/

PLEASE READ BOTH THE ARTICLE AND CITATIONS

http://trisomy21research.org/2017/07/20/701-2/

What about MECP2?

The MECP2 gene provides instructions for making a protein called MeCP2. This protein helps regulate gene activity (expression) by modifying chromatin, the complex of DNA and protein that packages DNA into chromosomes. The MeCP2 protein is present in cells throughout the body, although it is particularly abundant in brain cells.

In the brain, the MeCP2 protein is important for the function of several types of cells, including nerve cells (neurons). The protein likely plays a role in maintaining connections (synapses) between neurons, where cell-to-cell communication occurs. Many of the genes that are known to be regulated by the MeCP2 protein play a role in normal brain function, particularly the maintenance of synapses.

Researchers believe that the MeCP2 protein may also be involved in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. By cutting and rearranging mRNA molecules in different ways, the MeCP2 protein controls the production of different versions of certain proteins. This process is known as alternative splicing. In the brain, the alternative splicing of proteins is critical for normal communication between neurons and may also be necessary for the function of other types of brain cells.

Although this gene is mapped to the X chromosome, MicroRNA-155 plays a large role in the regulation of MECP2.

PLEASE READ

MeCP2 and Down Syndrome

https://www.jax.org/news-and-insights/2010/april/down-syndrome-is-caused-partly-by-gene-under-expression-not-just-over-expre

The bottom line is that every single substance included in this protocol directly targets over expressed genes, disrupted pathways and low levels of critical proteins.

THE FDA PROHIBITS EVEN INDIVIDUALS FROM MAKING MEDICAL CLAIMS FOR NUTRITIONAL SUPPLEMENTS. MENTION OF NUTRIONAL SUPPLEMENTS IS PROVIDED BASED ONLY ON THE ATTACHED RESEARCH TO EXPLAIN HOW THE HUMAN GENOME RESPONDS TO FOOD SUBSTANCES AND IS NOT INTENDED AS MEDICAL OR CURATIVE ADVICE.