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LESSON 11 SOD1, RCAN1 and CREB
Most citations used are taken from the NLM database and are in the public domain.
#lesson10 SOD1, RCAN1 and CREB
The SOD1 gene provides instructions for making an enzyme called superoxide dismutase, which is abundant in cells throughout the body. It is mapped to the critical region of Chromosome 21 and is over expressed in Down syndrome. This enzyme attaches (binds) to molecules of copper and zinc to break down toxic, charged oxygen molecules called superoxide radicals. The molecules are byproducts of normal cell processes, and they must be broken down regularly to avoid damaging cells. Unfortunately, the enzymes that work to breakdown these byproducts, Catalase and Glutathione Peroxidase are not located on the 21st chromosome and are present in the cells of persons with DS in much lower levels than SOD1. They simply cannot manage the excess of byproducts, The result is a failure of the antioxidant system.
Oxidative stress in DS May set the stage for the development of neurodegeneration and ultimately, Alzheimer’s Disease. It is the area of Alzheimer disease (AD) that oxidative stress in DS seems to have the most significance. By 40 years of age, virtually all individuals with DS show the characteristic neuropathological changes of AD including beta-amyloid (Aβ) plaques and neurofibrillary tangles . The accumulation of Aβ plaques in brain is seen across the lifespan in DS with appearance by 8 years of age or before. In most individuals with DS, the rate of Aβ deposition increases markedly between 35 and 45 years and becomes associated with neurofibrillary tangles.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408054/
PLEASE WATCH
What is oxidative stress and how does it cause cell damage?
https://m.youtube.com/watch?v=dlZ5ROca0KI
A common sense approach to oxidation in DS is the copious use of antioxidants. Trials in Down syndrome have not been impressive. There are several reasons for this. The main reason is that antioxidants, vitamins E, C and beta carotene are given in relatively small doses over a short period of time, followed by cognitive testing. Studies following this design are doomed to failure. Why? Because cognition in DS is inhibited by numerous gene excesses. Targeting a single gene over expression is simply insufficient. Utilizing these specific antioxidants is helpful but to see that, these studies should have been followed with urine tests for oxidation markers, not IQ testing. Even if providing antioxidants had no benefit on cognitive function, it cannot be ignored. It is not enough to say “if it can’t make a child smarter, it isn’t worth doing”, which is basically what some researchers have concluded. Your child is more than the measure of his or her IQ. What about rapid aging, damage to the immune system and vital organs? What about mitochondrial dysfunction and the rapid apoptosis of neurons? All are compromised by oxidative stress.
Although we do use standard antioxidants, we recognized that this approach would not be sufficient. Rather than just cleaning up free radicals down stream we improve this system by upregulating both Catalase and Glutathione Peroxidase. Elevating these as close to the levels of SOD1 as possible greatly enhances the effectiveness of the cells antioxidant triad. Additionally, we have introduced PQQ, which actually scavenges the Superoxide radical further diminishing the work load of both Catalase and Glutathione Peroxidase. The result is greater protection against oxidative stress.
PQQ a Superoxide scavenger
https://www.ncbi.nlm.nih.gov/pubmed/12383230
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408054/#!po=6.41026
Another way to help address oxidative stress in DS is through the use of Lycopene. Lycopene is extremely important in DS not only because it is a very effective antioxidant but it also inhibits ROS damage caused by the over expression RCAN1. Although PQQ, also has inhibitory effects on RCAN1, it is simply not enough, it is also important to address the damage caused by this gene.
https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201600530
https://www.ncbi.nlm.nih.gov/pubmed/23405535
Let’s move on to RCAN1.
The protein encoded by this gene effects calcineurin A and may disrupt 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/
PLEASE READ THE INHIBITORY EFFECTS OF LYCOPENE ON DAMAGE RELATED TO RCAN1
https://onlinelibrary.wiley.com/doi/full/10.1002/mnfr.201600530
Since Lycopene actually effects two major issues associated with DS, it should be part of your child’s protocol. In the future you will be able to purchase the micro encapsulated version of Nutrivene without Lycopene but, you must supplement it separately.
Since most of this lesson involves studies, I will keep the commentary short.
The rationale for the use of PQQ, antioxidants and Lycopene to prevent oxidative stress AND to handles excesses of RCAN1 are firmly outlined in the following research.
RCAN1, how does it harm your child? It exacerbates calcium loading neuronal apoptosis. This means it causes early death of neurons.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994074/
Contributes to immune dysfunction.
http://www.ncbi.nlm.nih.gov/pubmed/23644448
The over expression of RCAN1 inhibits memory and and learning.
http://www.ncbi.nlm.nih.gov/pubmed/22511596
Lycopene and RCAN1
https://www.ncbi.nlm.nih.gov/pubmed/?term=Lycopene+and+RCAN1
http://onlinelibrary.wiley.com/doi/10.1002/mnfr.201600530/abstract
Chronically high levels of RCAN1 lead to oxidative stress and neurodegenerative disease.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720382/
RCAN1 Damages mitochondria.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5248620/
PQQ and CREB mitochondria Genesis
https://www.researchgate.net/figure/PQQ-activates-CREB-and-induces-CREB-phosphorylation-at-serine-133-and-CREB-is-required_fig5_38040626
Activation of CREB at serine 133 decreases the protein level of RCAN1
http://www.sciencedirect.com/science/article/pii/S0014579308004043
PQQ activates CREB at serine 133.
The over expression of DYRK1a also substantially alters phosphorylation of CREB. The gene, DYRK1a is over expressed in DS and down regulated by this protocol by use of EGCG.
What is CREB
https://en.m.wikipedia.org/wiki/CREB
Nf-k and RCAN1
http://www.jbc.org/content/283/6/3392.full
Studies for the group on RCAN1
https://academic.oup.com/hmg/article/16/9/1039/687534
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095471
http://www.jbc.org/content/286/11/9049.full
https://www.ncbi.nlm.nih.gov/pubmed?term=28756311[pmid]. Multi gene therapy
DSCR AKA RCAN1 and DYRK1a
https://www.ncbi.nlm.nih.gov/pubmed?term=28674289[pmid]
Lycopene
https://www.ncbi.nlm.nih.gov/gene/1827
https://onlinelibrary.wiley.com/doi/abs/10.1002/mnfr.201600530
https://yonsei.pure.elsevier.com/en/publications/lycopene-inhibits-regulator-of-calcineurin-1-mediated-apoptosis-b
Lycopene and amyloid Protein
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579676/
https://www.ncbi.nlm.nih.gov/pubmed/22044877
Lycopene tested in hippocampus
https://www.ncbi.nlm.nih.gov/pubmed/22032970
Protection against Methyl mercury toxicity
https://www.ncbi.nlm.nih.gov/pubmed/24120987
Significantly ameliorates Memory deficits
https://www.ncbi.nlm.nih.gov/pubmed/28269786
This lesson demonstrates how over expressed genes are intertwined in the damage resulting to persons with Down Syndrome. This further emphasizes why a single target drug (effecting only one over expressed gene) will not be of any significant benefit to people with Down syndrome and why this comprehensive multi target therapy has proven to be effective.
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.
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