The Nurture Nature Project is dedicated to my brother John.
When I was 22 my younger half-brother, who was 19, developed adult onset schizophrenia. His suffering shook and devastated our family. Not wanting to accept, I returned to school and studied schizophrenia. I learned that for my brother there are drugs (with strong side effects) that can help ease the symptoms but there is no cure to this complex neuro-developmental illness.
Yet, science has moved forward at a breathtaking rate. We are post The Decade of The Brain and we have broken open Pandora’s DNA box. Genetic testing and other advanced technologies are bringing the many and varied pieces of the puzzle into higher relief.
Every year about 100,000 people in the U.S. are diagnosed with schizophrenia, twice as many as are diagnosed with Alzheimers. Suffering of this kind shatters families. The persistence of this horrifyingly cruel disease defies one’s sense of security in a scientifically, and medically advanced society. Scary things happen to really good people. Our family refuses any and all of the predatory, voodoo-esque, familial, social, and cultural shaming that festers in ignorance and fear. We give no permission to those who would hurt the spirit of those already suffering.
Shocking New Role Found for Immune System: Controlling Social Interactions, Josh Barney, Virginia.edu, July 16
A pregnant woman’s immune response could lead to brain disorders in her kids, Myka Estes, The Conversation, August 18, 2016. Myka Estes is a Postdoctoral Researcher in Neuroscience at University of California, Davis. (Note: Vitamin D has important immune-modulating properties which may help to establish a proper maternal immune response to the placenta.)
Preventive effects of minocycline in a neurodevelopmental two-hit model with relevance to schizophrenia Translational Psychiatry, April 5, 2016, Nature.com “In offspring of immune-challenged mothers, stress-induced inflammatory processes precede the adult onset of multiple behavioral dysfunctions. Here, we explored whether an early anti-inflammatory intervention during peripubertal stress exposure might prevent the subsequent emergence of adult behavioral pathology.”
Biological Insights from 108 Schizophrenia-Associated Genetic Loci, Schizophrenia Working Group of the Psychiatric Genomics Consortium, Nature, 511, 421–427 (24 July 2014)
“… there is a pressing need for better integration of the multiple research platforms in schizophrenia genetics, including
- biology computational models,
- neuroimaging and
- clinical correlations”
Ladislav Hosak, New Findings in the Genetics of Schizophrenia, World J. Psychiatry, 2013
#1 GOAL: PREVENT THE ILLNESS
As a woman who wanted a family but did not want to carry forward a possible hereditary problem, I started this research on a quest to protect a potential family and a potential child from unnecessary suffering. In the end I protected my children by not having any children. However, my younger sister has had a beautiful, very healthy child. She was able to take action from the start of her pregnancy based on top research findings in nutrigenomics to protect her child. I hope that this information gets to other women in similar situations who see that options are available.
Our family wants the main focus of research and money to be on finding the source and PREVENTING the illness.
MATERNAL IMMUNE ACTIVATION & FETAL BRAIN DEVELOPMENT
Khoshnan, A. & Patterson, P. H. (2012). Elevated IKKα Accelerates the Differentiation of Human Neuronal Progenitor Cells and Induces MeCP2-Dependent BDNF Expression. PLoS One, 7, e41794.
Garay, P. A., Hsiao, E. Y., Patterson, P. H. & McAllister, A. K. (2012). Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Brain, Behavior and Immunity, online.
FETAL NEURO DEVELOPMENT: FOLATE, B12, VITAMIN D, & CHOLINE
Among other jobs, folate, B12 and choline help protect the developing fetus from epigenetic modification and DNA damage. My mother has double allele gene SNPs (mutations), including MTHFR (l-methylfolate), VDR (vitamin D receptor), and PEMT (choline synthesis). These SNPs most likely decreased her body’s ability to provide folate, B12, vitamin D, and choline for her own wellbeing and for the healthy neuro-development of the child in her womb. These SNPs also likely left the fetus far less protected from further gene SNPs (mutations) in utero.
Why my mother has these SNPs is a vital question for another day.
Genomic and Epigenomic Insights into Nutrition and Brain Disorders, Nutrients, 2013, Margaret Joy Dauncey, Ph.D, University of Cambridge,
FOLATE GENES: MTHFR A1298C, B12, & METHYLATION
Most women have rightly been told to take folic acid supplements for pregnancy. In my mother’s case however, a double MTHFR gene SNP meant that, even though she WAS taking folic acid supplements during pregnancy, her body was far less able to turn the folic acid into the active form (5-methyltetrahydrofolate) needed for her health and the health of her developing fetus. MTHFR SNPs are also linked to lower vitamin B12 levels and autoimmunity diseases which also affect both the mother and the developing child. (See research below)
VITAMIN D GENES: VDR TAQ GENE SNP, INFECTION VULNERABILITY, & METHYLATION
My mother has double VDR (vitamin D receptor) Taq SNPs, which most likely leaves her lower in vitamin D in the winter, (she is very outdoor oriented during the other seasons). This may be one of the reasons that schizophrenia has been linked to the seasons and seasonal rain. A winter pregnancy of someone with a VDR mutation would leave the mother and child at risk of vitamin D deficiency. (Note: Vitamin D is linked to dopamine synthesis.) Low Vitamin D is also linked to higher influenza. In fact recent research shows that healthy vitamin D level can cut flu infection rates by half. And maternal flu exposure during the first half of pregnancy is associated with a three-fold increase in risk schizophrenia. Melanin also effects vitamin absorption and it too has been linked to schizophrenia. (See research below)
“vitamin D deficiency has several adverse effects, each of which contributes to increased risk for schizophrenia. These multiple adverse effects may include (1) disruptive effects on prenatal brain development94 as well as (2) harmful effects on maternal immune function that make the pregnant mother and her fetus or young infant more vulnerable to prenatal exposure to infections, thereby interacting synergistically with infections, such as influenza22,92 or toxoplasmosis,25,95,96 that previous research has linked to schizophrenia. Cannell et al97 reviewed evidence indicating that vitamin D is important for several aspects of immunological defense against infectious diseases and that seasonal variation in vitamin D deficiency may explain the marked seasonality of epidemic influenza. Moreover, as McGrath98 noted, both animal and in vitro experiments have demonstrated that administration of vitamin D can inhibit the intracellular growth of Toxoplasma gondii.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2669590/?report=reader
CHOLINE GENES: PEMT GENE SNP, CHOLINE, METHYLATION, & NEURODEVELOPMENT
Choline supplementation during pregnancy presents a new approach to Schizophrenia prevention, Science News, Jan. 15, 2013
SNPs, Nutrition (Choline), and DNA Methylation by Dr. Steven Zeisel M.D., PhD is a Kenan Distinguished University Professor in Nutrition and Pediatrics, University of North Carolina at Chapel Hill. (MD, Harvard, 1975; PhD, M.I.T., 1980)
Very few women know about the importance of choline for the child’s developing brain. In the majority of women, in the liver, PEMT enzymes help synthesize large amounts of choline during pregnancy for the child. Only recently have scientists discovered that many women are physiologically less able to make and provide choline for the fetus because of PEMT gene SNPs. And, in fact, it is quite a high percentage of women who have PEMT gene SNPs. It is VITALLY important that these women take choline supplements during pregnancy and breast feeding. (Note: Betaine is the choline-derived methyl donor.) (Note 2: Choline is supplemented in the form of lecithin, or phosphatidylcholine) (See research below)
“Well, we think that there are a number of genetic variants, single nucleotide polymorphisms (SNPs). These SNPs are extremely common in one carbon metabolism especially among caucasians and we’re reporting that these SNPs dramatically change whether you need choline or not and that people who have these metabolic inefficiencies related to these SNPs are on the order of 25 to 85 times more likely to develop liver and muscle damage when deprived of choline. And I think that they are also the people who are going to be more sensitive to making epigenetic modifications because they can’t either make choline or they use it faster and they don’t have as much for methyl groups to do methylation with. One of these genetic variations turns out to be in a gene that makes choline from scratch in the liver. It’s called PEMT. And that gene methylates phospholipid to form phosphatidyl-choline, and thereby choline. Turns out that gene is turned on in young women by estrogen. It’s there probably to get them through pregnancy when they have to build huge amounts of choline to build a good fetus. About half the population in North Carolina has a genetic variant, an SNP, in that gene that makes it unresponsive to estrogen and so they are reduced to “the sad state of man” and can’t make extra choline during pregnancy. So that probably makes those women and their babies the most susceptible to variations in choline and methyl groups during pregnancy and probably to some of these epigenetic phenomenon that we are looking at in terms of brain development.” Dr. Steven Zeisel M.D., PhD
FURTHER RESEARCH: FOLATE, METHYL DONORS, & BRAIN DEVELOPMENT
- Importance of methyl donors during reproduction. Zeisel SH. Am J Clin Nutr. 2009
- Genetic polymorphisms in methyl-group metabolism and epigenetics: lessons from humans and mouse models. Zeisel SH. Brain Res. 2008
- Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. Craciunescu CN,Brown EC, Mar MH, Albright CD, Nadeau MR, Zeisel SH., J Nutr. 2004
- Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency. Schwahn BC, Chen Z, Laryea MD, Wendel U, Lussier-Cacan S, Genest J Jr, Mar MH, Zeisel SH, Castro C, Garrow T, Rozen R. FASEB J. 2003
- Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. Niculescu MD, Zeisel SH. J Nutr. 2002
- Severe folate deficiency causes secondary depletion of choline and phosphocholine in rat liver. Kim YI, Miller JW, da Costa KA, Nadeau M, Smith D, Selhub J, Zeisel SH, Mason JB. J Nutr. 1994
FURTHER RESEARCH: VDR GENE, PRENATAL VITAMIN D & SCHIZOPHRENIA
- Evidence for phenoypic plasticity in response to photic cues and the connection with genes of risk in schizophrenia. Frontiers in Behavioral Neuroscience, 2013 Miller CL.
- The gene encoding the melanin-concentrating hormone receptor 1 is associated with schizophrenia in a danish case-control sample, Psychiatr Genet. 2012 Demontis D, Nyegaard M, Christensen JH, Severinsen J, Hedemand A, Hansen T, Werge T, Mors O, Børglum AD.
- Developmental vitamin D deficiency alters the expression of genes encoding mitochondrial, cytoskeletal and synaptic proteins in the adult rat brain. J. Steroid Biochem. Mol. Biol. Eyles D., Almeras L., Benech P., Patatian A., Mackay-Sim A., McGrath J., et al. (2007). [PubMed][Cross Ref]
- Relation of schizophrenia prevalence to latitude, climate, fish consumption, infant mortality, and skin color: A Role for Prenatal Vitamin D Deficiency and Infections? Schizophrenia Bulletin, Oxford University Press, 2009 Dennis K. Kinney, Pamela Teixeira, …and Emerald Huang “The increase in prevalence with latitude was greater for groups with low fish consumption, darker skin, and higher infant mortality—consistent with a role of prenatal vitamin D deficiency in schizophrenia.”
FURTHER RESEARCH: CHOLINE & BRAIN DEVELOPMENT
- Nutrition in Pregnancy: The argument for including a source of choline, Zeisel, SH, International Journal for Women’s Health, 2013
- Dietary choline deficiency causes DNA strand breaks and alters epigenetic marks on DNA and histones, Zeisel SH, Mutation Research 2012
- The nutrigenetics and nutrigenomics of dietary requirement for choline, Corbin KD, Zeisel SH, Progress in Molecular Biology and Translational Science, 2012
- The supply of choline is important for fetal progenitor cells. Zeisel SH.Semin Cell Dev Biol. 2011
- Aberrant estrogen regulation of PEMT results in choline deficiency-associated liver dysfunction. Resseguie ME, da Costa KA, Galanko JA, Patel M, Davis IJ, Zeisel SH. J Biol Chem. 2011
- Dietary choline reverses some, but not all, effects of folate deficiency on neurogenesis and apoptosis in fetal mouse brain. Craciunescu CN, Johnson AR, Zeisel SH. J Nutr. 2010
- Dietary docosahexaenoic acid supplementation modulates hippocampal development in the Pemt-/- mouse. da Costa KA, Rai KS, Craciunescu CN, Parikh K, Mehedint MG, Sanders LM, McLean-Pottinger A, Zeisel SH. J Biol Chem. 2010
- Are dietary choline and betaine intakes determinants of total homocysteine concentration? Lee JE, Jacques PF, Dougherty L, Selhub J, Giovannucci E, Zeisel SH, Cho E. Am J Clin Nutr. 2010
- A grand challenge for nutrigenomics. Zeisel SH. Front Genet. 2010
- High intakes of choline and betaine reduce breast cancer mortality in a population-based study. Xu X, Gammon MD, Zeisel SH, Bradshaw PT, Wetmur JG, Teitelbaum SL, Neugut AI, Santella RM, Chen J. FASEB J. 2009
- Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the Calbindin 1 gene. Mihai G Mehedint, Mihai D Niculescu, Corneliu N Craciunescu, Steven H Zeisel, The FASEB Journal, 2009
- The role of gender and genetic polymorphisms in de novo choline synthesis, Mary E. Resseguie, 2008
- Gene response elements, genetic polymorphisms and epigenetics influence the human dietary requirement for choline. Zeisel SH. IUBMB Life. 2007
- Diethanolamine alters proliferation and choline metabolism in mouse neural precursor cells. Niculescu MD, Wu R, Guo Z, da Costa KA, Zeisel SH. Toxicol Sci. 2007
- Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains, Niculescu MD, Craciunescu CN, Zeisel SH, FASEB J. 2006
- The fetal origins of memory: the role of dietary choline in optimal brain development. Zeisel SH. J Pediatr. 2006
- Diethanolamine alters neurogenesis and induces apoptosis in fetal mouse hippocampus. Craciunescu CN, Wu R, Zeisel SH. (Diethanolamine is a wetting agent used in a number of consumer products, such as shampoos, cosmetics, and pharmaceuticals.) FASEB J. 2006
- Common genetic polymorphisms affect the human requirement for the nutrient choline. da Costa KA, Kozyreva OG, Song J, Galanko JA, Fischer LM, Zeisel SH. FASEB J. 2006
- Genetic variation of folate-mediated one-carbon transfer pathway predicts susceptibility to choline deficiency in humans. Kohlmeier M, da Costa KA, Fischer LM, Zeisel SH. Proc Natl Acad Sci U S A. 2005
- Maternal dietary choline availability alters the balance of netrin-1 and DCC neuronal migration proteins in fetal mouse brain hippocampus. Albright CD, Mar MH, Craciunescu CN, Song J, Zeisel SH. Brain Res Dev Brain Res. 2005
- Choline availability modulates human neuroblastoma cell proliferation and alters the methylation of the promoter region of the cyclin-dependent kinase inhibitor 3 gene. Niculescu MD, Yamamuro Y, Zeisel SH. J Neurochem. 2004
- Deletion of the Pemt gene increases progenitor cell mitosis, DNA and protein methylation and decreases calretinin expression in embryonic day 17 mouse hippocampus. Zhu X, Mar MH, Song J, Zeisel SH. Brain Res Dev Brain Res. 2004
- Choline availability during embryonic development alters progenitor cell mitosis in developing mouse hippocampus. Craciunescu CN, Albright CD, Mar MH, Song J, Zeisel SH. J Nutr. 2003
- Phosphatidylethanolamine N-methyltransferase (PEMT) knockout mice have hepatic steatosis and abnormal hepatic choline metabolite concentrations despite ingesting a recommended dietary intake of choline. Zhu X, Song J, Mar MH, Edwards LJ, Zeisel SH. Biochem J. 2003
- Inhibitors of choline uptake and metabolism cause developmental abnormalities in neurulating mouse embryos. Fisher MC, Zeisel SH, Mar MH, Sadler TW. Teratology. 2001
- Maternal choline availability alters the localization of p15Ink4B and p27Kip1 cyclin-dependent kinase inhibitors in the developing fetal rat brain hippocampus. Albright CD, Mar MH, Friedrich CB, Brown EC, Zeisel SH. Dev Neurosci. 2001
- Maternal dietary choline availability alters mitosis, apoptosis and the localization of TOAD-64 protein in the developing fetal rat septum. Albright CD, Friedrich CB, Brown EC, Mar MH, Zeisel SH. Brain Res Dev Brain Res. 1999
- Choline deficiency-induced apoptosis in PC12 cells is associated with diminished membrane phosphatidylcholine and sphingomyelin, accumulation of ceramide and diacylglycerol, and activation of a caspase. Yen CL, Mar MH, Zeisel SH. FASEB J. 1999
- Choline deficiency causes increased localization of transforming growth factor-beta1 signaling proteins and apoptosis in the rat liver. Albright CD, Zeisel SH. Pathobiology. 1997
- Cholinergic neurones and memory. Zeisel S, Reinstein D, Corkin S, Growdon J, Wurtman R. Nature. 1981
So many terrible developmental illnesses can be prevented! Doctors need to test women early for these gene SNPs and make sure they are informed about taking supplements that provide the active form and appropriate doses of these vitamins during pregnancy and breast feeding.
CHOLINE IN COMMON FOODS
WE CAN PREVENT
We can prevent now! Please share this story with doctors and health care providers. Please help spread the word. We can test and treat those women who are at greater risk for giving birth to a child with neurodevelopmental illness, whether latent schizophrenia or another neurodevelopmental disease, due to addressable SNP related biological dysfunction. Many SNP linked dysfunctional enzymes can be bypassed through Nutrigenomic means (i.e. choline for a PEMT polymorphism or the metabolically active form of folate for MTHFR mutations)
NOTE TO DOCTORS AND HEALTHCARE PRACTITIONERS
Please help forward this movement to test women early, before conception, for choline, vitamin D, folate, and other related gene SNPs. Catch this early and help these women get the active form of the vitamins they and their babies need. You can help prevent terrible and unecessary suffering.
SNPs, Nutrition (Choline), and DNA Methylation by Dr. Steven Zeisel M.D., PhD is a Kenan Distinguished University Professor in Nutrition and Pediatrics, University of North Carolina at Chapel Hill. (MD, Harvard, 1975; PhD, M.I.T., 1980)
NOTE TO SCHIZOPHRENIA RESEARCH SCIENTISTS
Thank you profoundly for all the time and effort you have put into understanding this illness! I have one request that I place forth with not-so-niave hope. This one thing would change the world for families with an ill member. I would be deeply grateful if each of you, or each lab website would offer the following. Yes it is a lot to ask. I am aware. :
- Steps you would take if you had a loved one with schizophrenia
- Steps you would take if you developed the illness yourself
- What you would do if you were Surgeon General of the United States to prevent it.
(Of course, attach the mile long legal disclaimer.) Few researchers, so deeply immersed in their labs, take the time or emotional energy to do this. Yet, it is you, the researchers on the leading edge that we need to hear from. A small honest personal statement could help so many. We know there is no cure yet. I thank you ahead of time.
There have been many promising advances in the field over the last decade. I believe we will have true life changing breakthroughs in the next 5 years.
MORE ABOUT MY BROTHER
At the same time that I saw my brother’s suffering and faced some of the harshest realities of life with and through him, I also was given the ongoing gift of meeting people with beautiful hearts; people who reached out to my mother, who treat my brother with kindness and respect, who helped him through some of his most difficult times.
My brother is sensitive and kind. He has deep empathy. This illness is dark and cruel, a terrible form of human torture, that has contorted his very existence. He has endured great personal and social suffering. Yet, amazingly he still loves life!
I look forward to the day we erase this illness from the planet. We are able to do so much to protect our loved ones and to nourish healthy development. Why would we possibly not take the opportunity?
“When we remember we are all mad, the mysteries disappear and life stands explained.” – Mark Twain
GENETIC TESTING & PERSONALIZED NUTRIENT SUPPLEMENTATION
My brother has a wonderful doctor. He has worked to help my brother stay safe, adjust, and live in this world. My brother is on what is considered the best pharmaceutical drug combination for his symptoms. But, I think we can do much more.
Today we can begin to address each person’s illness in a personalized manner, piece by piece, risk SNP by risk SNP, nutrient deficiency by nutrient deficiency. No this is NOT easy. (Amy Yasko, PhD is doing this for children with Autism dramyyasko.com ) The possibility of healing our loved ones “lost in translation” is vastly greater. For those who have been left long in the dark, do not look back. Take courage. You are not alone.
YOU ARE NOT YOUR GENES
Yet, understanding some of your genetic makeup can facilitate a proper diagnosis and the healing process. Understanding some of the factors which may be compounding the illness can definitely help you make better informed health decisions. I highly recommend genetic testing or, at the very least, methylation cycle gene testing. To date, the least expensive testing is through 23andme.
23andme Genetic Testing : They send you a little tube and a return box with return address and you just have to spit in the tube, place it in the box and mail back. They analyze a vast number of SNPs for only $99. Truly a modern day miracle.
Methylation Analysis : Once the data is returned, Send it through the free online geneticgenie.com Methylation Analysis program. Just click on the link and you will see the directions. This can tell you if you have Methylation Cycle SNPs. And it will give you a brief explanation of possible effects of each SNP. DNA Methylation can be supported by vitamins such as B12, Folate, SAMe, and B6, depending on what SNPs you have.
A Detox gene SNP analysis is also available. However it is still in its early development stage and the analysis is missing a lot of the explanatory info.
After getting his DNA analyzed by 23andme, (see info below) we were able to pinpoint some of his methylation cycle gene SNPs / variants / mutations.
The following information comes from the important work of Dr. Amy Yasko, who has helped many children with autism address their methylation cycle SNPS through nutrigenomic therapy. http://www.dramyyasko.com/ I am deeply grateful for Dr. Amy Yasko. Love, care, and complete dedication shines through all she does to help children heal.
Of course the following nutrient supplement suggestions are not a cure. However, each has solid potential to help with some symptoms.
MTHFR Gene SNPs: One SNP/variant is in a gene that codes for methylenetetrahydrofolate reductase (MTHFR) and it impairs his ability to process folate. He has a problem converting the folic acid and folate from foods and vitamins into the metabollically active form of folate needed by his body and brain. ( Genotype plays role in schizophrenia response to folate, Clinical Psychiatry News) Because of this he needs to take 5,10 Methytetrahydrofolate. This MTHFR SNP can lead to elevated levels of homocysteine. So he will also be tested for this.
COMT & VDR Taq Gene SNPs: According to Dr. Amy Yasko, many people with the COMT and VDR taq SNPs (epigenetic mutations) combination have problems accepting methyl donors. Because of this, my brother needs to take the adenosyl form of vitamin B12 in addition to the methyl form. If you are interested in learning about Nutrigenomic therapy continue reading.
Genetic tests reveal need for vitamins is the story of a woman, Sylvia Escott-Stump, MA, RD, LDN, who helped her son who developed schizophrenia. After the schizophrenia diagnosis, Dr Escott-Stump and her two children were genetically tested. She had one copy of a gene variant associated with problems in converting folate into the form needed by the body. Her children both had two copies. “He finished his degree, got a job and he’s gone to graduate school. He was hospitalised twice and we thought he would never be employable, would never finish college.”
Dietary influences on neurotransmission. Zeisel SH. Adv Pediatr. 1986 Nutrients, neurotransmitters and infant behavior. Yogman MW, Zeisel SH. Am J Clin Nutr. 1985 Neurotransmitter precursors and brain function. Conlay LA, Zeisel SH. Neurosurgery. 1982
PREVENTION IS THE ANSWER. HOWEVER, A GIRL CAN DREAM.
Reverse Engineering of causal genetic variations. Genome editing technologies that target
single nucleotide polymorhisms. http://zlab.mit.edu/assets/reprints/Cong_L_Science_2013.pdf S. pyogenes CRISPR system
(Yes to a precise targeted genetic manipulation to prevent neurodevelopmental illnesses)
Restoration of hippocampal growth hormone reverses stress-induced
hippocampal impairment. Front Behav Neurosci. 2013. Vander Weele CM, Saenz C, Yao J, Correia SS, Goosens KA. Source: Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research, Massachusetts Institute of Technology Cambridge, MA, USA. Abstract Though growth hormone (GH) is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning, and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience
EPIGENETICS & DNA METHYLATION: FOLATE, CHOLINE, B12, BETAINE, AND METHIONINE
In the following edited version of an exerpt from NOVA’s Ghost in Your Genes, Randy Jirtle, a geneticist in the Department of Radiation Oncology at Duke University, answered viewer questions about epigenetics. (August 2 and November 1, 2007 (see below)). For more information, please go to Epigenetic Therapy, A Tale of Two Mice, and Links & Books.
AUGUST 2, 2007
Q: If environmental factors can influence the gene expression in offspring, can that process be reversed or altered by other factors (diet, drugs, gene therapy, etc.) after the offspring are born? Vladimir Sanchez, San Francisco, California
A: We have shown that during early fetal development, maternal nutrient supplements of methyl-donating substances (folic acid, choline, vitamin B12, and betaine) or genistein, found in soy products, can counteract the reduction in DNA methylation caused by BPA. Nevertheless, we have not yet tested if exposure to these nutrient supplements can reverse the negative effects of BPA in adulthood.
Weaver et al. (Nat. Neurosci. 7: 847-854, 2004) at McGill University, however, have shown recently that maternal nurturing behavior can stably alter the epigenotype in rat pups soon after birth. Moreover, these epigenetic changes are reversible in adulthood following methionine supplementation or treatment with histone deacetylase (HDAC) inhibitors (Weaver et al. Proc. Natl. Acad. Sci. USA 103: 3480-3485, 2006). Thus, data supporting the reversal of environmentally induced epigenetic changes via dietary supplementation or pharmaceutical therapy in adulthood is mounting. http://www.methdb.de/
Q: Can a person manipulate his or her environment in such a way as to maximize his or her IQ and minimize his or her genetic disposition for mental illness? Also, have scientists been able to reverse a negative gene expression brought on by epigenetics such as the one expressed in the twin mice? Anonymous
A: Choline supplementation during pregnancy in rats increases learning ability, enhances synaptic function, and offers protection from neurotoxicity (Li, Q., J. Neurophysiol. 91: 1545-1555, 2004). These effects of choline on neurological function most likely involve altered gene expression and associated changes in nerve cell growth and differentiation mediated by epigenetic changes, such as DNA methylation. Although the animal data on choline and hippocampal development are compelling, studies are needed to determine whether choline supplementation during pregnancy has the same effect in humans. (For review see: Zeisel, S.H., J. Pediatr. 149 [Suppl. 5]: S131-5136, 2006.) It is unknown if food supplements or epigenetic drug therapy in adulthood can reverse an epigenetically regulated negative effect on neural function in humans. http://www.methdb.de/
Q: There has been much alarming research linking several chemicals to negative genetic and epigenetic changes in the womb. How do we translate this into policy, hopefully preventing harm to future generations across the board? And how do we decide which chemicals to rally against? Jill McElheney, Winterville, Georgia
A: … Current risk-assessment procedures for evaluating the potential health effects of environmental exposures do not explicitly address epigenetic changes. It is also important that other endocrine-disrupting agents like BPA be assessed for their ability to epigenetically alter gene expression during early development because this is the stage of life when cellular function is most vulnerable to epigenetically active environmental factors. http://www.methdb.de/
Q: I see how diet and habits such as smoking could affect our epigenome, but has any research been done on humans or lab mice on how our moods might affect epigenetics? Does a healthy body rely upon positive thinking? Sarah Alexander, Graton, California
A: Fear conditioning in the rat results in brain DNA methylation coupled with the silencing of the memory suppressor gene, PP1 (Protein phosphatase 1), and DNA demethylation and activation of the synaptic plasticity gene, RELN (Reelin) (Miller and Sweatt, Neuron 53: 857-869, 2007)… http://www.methdb.de/
Q: I have two boys who were born in Korea to different mothers. They are not related at all, but they both have autism and an almost identical list of allergies. I have two questions/comments. Could this have been caused by stress from their having moved from foster home to foster home to here? Or could this have something to do with the Korean War? I know there is speculation with Vietnam and Agent Orange, but what about other wars? Cheryl, Visalia, California
A: Rat studies show that maternal nurturing of the offspring after birth reduces their response to stress by altering the epigenome in the brain (Szyf et al., Reprod. Toxicol. 24: 9-19, 2007). There is also evidence in humans that prenatal exposure to maternal stress induced by war can increase the risk of subsequently developing schizophrenia (van Os, et al.,Br. J. Psychiatry 172: 324–326, 1998)… http://www.methdb.de/
Q: As a college student who is currently applying to medical school, what implications could epigenetics have on disease treatment and prevention? Do you see traditional medicine changing and being replaced with a more genetic basis? Jake Kenyon, Lawrence, Kansas
A: …Already epigenetic therapeutic approaches, involving DNA methylation inhibition and histone deacetylase inhibition, are being used to treat cancer (Yoo and Jones, Nat. Rev. Drug Discov. 5: 37-50, 2006). Epigenetic therapies are also undergoing increased development to directly target sites in the genome, including the directed silencing of specific oncogenes via DNA methylation (Hoffman and Hu, Cell Mol. Neurobiol. 26: 425-438, 2006). Therefore, you should have more agents that target specific regions of the epigenome for the prevention and treatment of human diseases and disorders than are now available. However, to successfully utilize these novel drugs, you will need a good working knowledge of epigenetics, nutrition, and toxicology. http://www.methdb.de/
CONCLUDING REMARKS FROM DR. JIRTLE
Human epidemiological and animal experimental data indicate that the risk of developing adult-onset diseases is influenced by persistent adaptations to prenatal and early postnatal exposure to environmental factors. Moreover, the link between what we are exposed to during pregnancy and disease formation in adulthood appears to involve epigenetic modifications like DNA methylation. Therefore, to gain a clearer understanding of human disease formation, genes whose function is particularly sensitive to environmentally induced epigenetic modification need to be identified.
Genomic imprinting is an epigenetic form of gene regulation that results in monoallelic, parent-of-origin dependent gene expression (Jirtle and Weidman, Am. Sci. 95: 143-149, 2007). The functional haploid state of imprinted genes makes them susceptibility loci for diseases since a single genetic or epigenetic mutation can alter their function. http://www.methdb.de/
- Schahram Akbarian MD, PhD – Professor of Neuroscience and psychology, Icahn School of Medicine at Mount Sinai, (Psychiatric Epigenetics)
- Armin Alaedini, PhD – Columbia University (Neuroimmunology, Autoimmunity, Gluten Sensitivity & Schizophrenia) (“anti-gliadin antibodies bind to neuronal synapsin I”)(“development of an immune-mediated disease process directed at the nervous system”)(“Anti-neural antibody reactivity in patients with a history of Lyme borreliosis”)(“Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia, Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F, Yang S, Krivogorsky B, Alaedini A, Yolken R.”)
- Åsa Blomström, M.D. – Karolinska Institute (“Maternal gluten sensitivity linked to schizophrenia risk in children”)(“Maternal Antibodies to Dietary Antigens and Risk for Nonaffective Psychosis in Offspring, Karlsson H, Blomström Å, Wicks S, Yang S, Yolken RH, Dalman C.”)
- Christina Dalman, M.D., Ph.D. – Johns Hopkins University, (“Maternal gluten sensitivity linked to schizophrenia risk in children”) (“Maternal Antibodies to Dietary Antigens and Risk for Nonaffective Psychosis in Offspring, Karlsson H, Blomström Å, Wicks S, Yang S, Yolken RH, Dalman C.”)
- Faith Dickerson, PhD. – Johns Hopkins School of Medicine (“DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1, Kamiya, A.,Tomoda, T., Chang, J., Takaki, M., Zhan, C., Morita, M., Cascio, M.B., Elashvili, S., Koizumi, H., Takanezawa, Y., Dickerson Faith, Yolken, R., Arai, H., Sawa, A.”)(“C-reactive protein is associated with cognitive impairment but not psychiatric symptoms in individuals with schizophrenia, Dickerson Faith, Stallings, C., Origoni, A., Sullens, A., Boronow John, Yolken, R.”)(“Cytomegalovirus and Schizophrenia, Torrey, E.F., Leweke, F.M., Schwartz, M.J, Mueller, N., Bachmann, S., Schroeder, J., Dickerson Faith, Yolken, R.H.”)
- Håkan Karlsson, Ph.D. – Karolinska Institute (“…maternal antibodies to both infectious and dietary antigens as well as altered levels of acute phase proteins in the neonatal blood”)(“Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice.”)(“Maternal gluten sensitivity linked to schizophrenia risk in children”)(“Maternal Antibodies to Dietary Antigens and Risk for Nonaffective Psychosis in Offspring, Karlsson H, Blomström Å, Wicks S, Yang S, Yolken RH, Dalman C.”)
- Lin Mei, PhD Georgia Regents University (mechanisms of synapse formation, neurotransmission, and synaptic plasticity) Schizophrenia joins reversable neurodevelopmental Disorders http://www.bioworld.com/content/schizophrenia-joins-reversible-neurodevelopmental-disorders-0
- Mihai Niculescu, MD, PhD, University of North Carolina-Chapel Hill (Perinatal Choline, Folate, +. Mother’s diet and fetal brain development)(“Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline.”)(“Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency.”)(“Choline deficiency alters global histone methylation and epigenetic marking at the Re1 site of the calbindin 1 gene”)(“Choline availability modulates human neuroblastoma cell proliferation and alters the methylation of the promoter region of the cyclin-dependent kinase inhibitor 3 gene”)(“Dietary choline deficiency alters global and gene-specific DNA methylation in the developing hippocampus of mouse fetal brains.”)(“Choline deficiency increases lymphocyte apoptosis and DNA damage in humans.”)
- Emily Severence, PhD – Johns Hopkins School of Medicine (Stanley Division of Developmental Neurovirology, How perinatal and subsequent exposure to certain foods and microbes might contribute to psychiatric symptoms and pathologies, Impact of immune factors on the gut-brain axis)(“Complement C1Q Formation of Immune Complexes with Milk Caseins and Wheat Glutens in Schizophrenia”) (“The Toxoplasma MAG1 peptides induce sex-based humoral immune response in mice and distinguish active from chronic human infection.“)(“Anti-gluten immune response following Toxoplasma gondii infection in mice.“)
- Helen Stolp, PhD – University of Oxford (“Role of developmental inflammation and blood-brain barrier dysfunction in neurodevelopmental and neurodegenerative diseases”)(“Neuropoietic cytokines in normal brain development and neurodevelopmental disorders.”)
- Ian C. G. Weaver, PhD, McGill University “nurturing our epigenetic nature” (“perinatal exposure to steroid (stress) hormones on the developing mammalian forebrain”) (“Epigenetic programming of stress responses and trans-generational inheritance through natural variations in maternal care: a role for DNA methylation in experience-dependent (re)programming of defensive responses.”)(“The transcription factor NGFI-A mediates epigenetic programming: altering epigenetic marks by immediate-early genes.”)
- Susanne Wicks, Ph.D. – Johns Hopkins University (“Maternal Antibodies to Dietary Antigens and Risk for Nonaffective Psychosis in Offspring, Karlsson H, Blomström Å, Wicks S, Yang S, Yolken RH, Dalman C.”)
- Robert Yolken, MD, Johns Hopkins Children’s Hospital Pediatric Neurovirology (“Abnormalities of neurotransmitter and neuropeptide systems in human neuroepithelioma cells infected by three Toxoplasma strains.“)(“Discordant patterns of bacterial translocation markers and implications for innate immune imbalances in schizophrenia.“)(“Elevated gliadin antibody levels in individuals with schizophrenia.“)(“The Toxoplasma MAG1 peptides induce sex-based humoral immune response in mice and distinguish active from chronic human infection.“)(“Anti-gluten immune response following Toxoplasma gondii infection in mice, Karlsson H, Blomström Å, Wicks S, Yang S, Yolken RH, Dalman C.”)(“DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1, Kamiya, A.,Tomoda, T., Chang, J., Takaki, M., Zhan, C., Morita, M., Cascio, M.B., Elashvili, S., Koizumi, H., Takanezawa, Y., Dickerson Faith, Yolken, R., Arai, H., Sawa, A.”)(“C-reactive protein is associated with cognitive impairment but not psychiatric symptoms in individuals with schizophrenia, Dickerson Faith, Stallings, C., Origoni, A., Sullens, A., Boronow John, Yolken, R.”)(“Cytomegalovirus and Schizophrenia, Torrey, E.F., Leweke, F.M., Schwartz, M.J, Mueller, N., Bachmann, S., Schroeder, J., Dickerson Faith, Yolken, R.H.”)(“Markers of gluten sensitivity and celiac disease in recent-onset psychosis and multi-episode schizophrenia, Dickerson F, Stallings C, Origoni A, Vaughan C, Khushalani S, Leister F, Yang S, Krivogorsky B, Alaedini A, Yolken R.” “Individuals with bipolar disorder have increased levels of IgG antibodies to gliadin. However, such antibody increase is not accompanied by an elevation in IgA antibodies to gliadin or the celiac disease-associated antibodies against deamidated gliadin and tTG. “)
- Steven H. Zeisel, MD, PhD, University of North Carolina-Chapel Hill (“The supply of choline is important for fetal progenitor cells.”)(“The nutrigenetics and nutrigenomics of the dietary requirement for choline.”)(“Choline-gene interactions: a model for study of the nutrigenetic effects of functional foods on brain development.”)(“Choline, homocysteine, and pregnancy.”)(“Brain development and choline, the other methyl donor.”) (“Choline and phosphatidylcholine.”)(“Choline and Lecethin”)
- Biesiekierski JR – Monash University, Australia (“Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Biesiekierski JR, Newnham ED, Irving PM, Barrett JS, Haines M, Doecke JD, Shepherd SJ, Muir JG, Gibson PR.”)
- Paula A. Garay – Center for Neuroscience,University of California Davis (“Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Garay PA, Hsiao EY, Patterson PH, McAllister AK.”)(“Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders. Garay PA, McAllister AK”)
- A. Kimberly McAllister – Center for Neuroscience,University of California Davis Cellular and molecular mechanisms of synapse formation and plasticity in cortical development and disease) (“Maternal immune activation causes age- and region-specific changes in brain cytokines in offspring throughout development. Garay PA, Hsiao EY, Patterson PH, McAllister AK.”)(“Novel roles for immune molecules in neural development: implications for neurodevelopmental disorders. Garay PA, McAllister AK”) (“Neuroligin 1: a cell adhesion molecule that recruits PSD-95 and NMDA receptors by distinct mechanisms during synaptogenesis, Barrow SL, Constable JR, Clark E, El-Sabeawy F, McAllister AK*, and Washbourne PW* “)(“Estradiol targets pre and postsynaptic proteins to induce glutamatergic synapse formation in cultured hippocampal neurons via an estrogen receptor-mediated process, Jelks, KAB, Wylie RL, Floyd CL, McAllister AK, and Wise PM.”)
- Urs Meyer, MD Laboratory of Behavioural Neurobiology, Zurich, Switzerland (“maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) gestation”,”PolyI:C-induced immune activation, in early but not late gestation, caused marked enlargement of lateral ventricles in adulthood, without affecting total white and grey matter volumes. This early exposure disrupted sensorimotor gating, in the form of prepulse inhibition. Identical immune challenge in late gestation resulted in significant expansion of 4th ventricle volume but did not disrupt sensorimotor gating.”)(“Prenatal Immune Activation Induces Maturation-Dependent Alterations in the Prefrontal GABAergic Transcriptome, Juliet Richetto1, Francesca Calabrese1, Marco A. Riva1,2,4 and Urs Meyer“)(“Immuno-inflammatory, oxidative and nitrosative stress, and neuroprogressive pathways in the etiology, course and treatment of schizophrenia., Anderson G, Berk M, Dodd S, Bechter K, Altamura AC, Dell’osso B, Kanba S, Monji A, Fatemi SH, Buckley P, Debnath M, Das UN, Meyer U, Müller N, Kanchanatawan B, Maes M.”)(“Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models, Eyles D, Feldon J, Meyer U.”)(“Personalized medicine: a personal view.“)(“Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments.,Vuillermot S, Joodmardi E, Perlmann T, Ögren SO, Feldon J, Meyer U.”)(“Priming of metabolic dysfunctions by prenatal immune activation in mice: relevance to schizophrenia., Pacheco-López G, Giovanoli S, Langhans W, Meyer U.”)(“Developmental neuroinflammation and schizophrenia., Meyer U.”)
- Feldon J., Laboratory of Behavioural Neurobiology, Zurch, Switzerland (“Schizophrenia: do all roads lead to dopamine or is this where they start? Evidence from two epidemiologically informed developmental rodent models, Eyles D, Feldon J, Meyer U.”) (“Prenatal immune activation interacts with genetic Nurr1 deficiency in the development of attentional impairments.,Vuillermot S, Joodmardi E, Perlmann T, Ögren SO, Feldon J, Meyer U.”)(“Disruption of Glycine Transporter 1 Restricted to Forebrain Neurons Is Associated with a Procognitive and Antipsychotic Phenotypic Profile, Yee, B., Balic, E., Singer, P., Schwerdel, C. Grampp, T., Gabernet, L., Knuesel, I., Benke, D., Feldon, J., Mohler, H., Boison, D.”)
- Samaroo D., Weill Medical College of Cornell University (“Novel immune response to gluten in individuals with schizophrenia., Samaroo D, Dickerson F, Kasarda DD, Green PH, Briani C, Yolken RH, Alaedini A.”)
- Patrick Sullivan, MD FRANZCP (University of North Carolina, Director Psyciatric Genomics, Professor of Psychiatry, Foreign Adjunct Profressor Karolinska Institute) http://sullivanlab.unc.edu/
- Pamela A. Carpentier
- Dohan FC
- Also see Experts: Methylation http://www.experts.scival.com/reachnc/conceptSearch.asp?n=Methylation&addById=13618&prefix=msh
———————————————————————————– Gluten Sensitivity Testing: A complete gluten sensitivity /celiac panel includes the following blood tests:
- anti-gliadin (AGA), IgA and IgG (increased significance for neurological manifestion of gluten sens)
- anti-deamidated gliadin (DGP), IgA and IgG (more specific to celiac disease)
- anti-TG2 (TG2), IgA and IgG (if positive, very suggestive of celiac disease)
- total serum IgA (rules out IgA deficiency)
Being used in research:
- anti-TG6 (TG6), IgA and IgG (for neurological manifestion)
- anti-TG3 (TG3), IgA and IgG (for dermatitis herpetiformis)
* * * IMPORTANT about Anti-gliadin antibodies * * * A newer test, anti-deamidated gliadin, has been developed over the last several years and some labs are beginning to automatically substitute it instead of the original antigliadin antibody tests. The newer test is more specific to “celiac disease / villous atrophy”, which is not helpful when looking for gluten sensitivity manifesting in non-gut ways (like neurological disease or other autoimmune disease), or when there are gut symptoms that have not yet caused villous atrophy. BE SURE your doctor orders the original antigliadin tests. DOUBLE CHECK that the right tests are ordered, and DOUBLE CHECK that the right tests were run. You want anti-gliadin IgA and anti-gliadin IgG, over anti-deamidated gliadin…. or all of them! Further explanation of the tests: To save cost, the celiac panel is often reduced to a single test… the anti-tTG IgA. Insist on more thorough testing than this single screening test! Total serum IgA should always be run to rule out a condition called IgA deficiency. The other IgA tests are not reliable measures in someone who does not make enough IgA. Many “experts” consider the original antigliadin test as optional and outdated. It is said that antigliadin antibodies are not specific to celiac disease, but they are often the first to show and are of increased significance for those who may have gluten sensitivity manifesting as neurological disease. You want it! The anti-endomysial antibody test is very specific for villous atrophy, but it has been replaced by the newer anti-tTG test. In a perfect world, anti-tTG and anti-endomysial will be in alignment, but in the real world sometimes one is positive and other not. A thorough doctor will run both. Reticulin antibodies have fallen out of favor even longer ago, but I do know of one person diagnosed with biopsy proven celiac disease who had only an isolated positive anti-reticulin antibody. http://www.lymeneteurope.org/forum/viewtopic.php?f=11&t=3648 ——————————————————————————————————————– Scientists are working to bring the pieces of the puzzle together. Among other findings:
- Prenatal exposure to lead and other toxins can increase the risk.
- Prenatal infection and increased HSV-2 IgG levels are associated with increased risk for schizophrenia.
- A mother’s autoimmunity, untreated celiac, and/or gluten sensitivity can increase the risk.
- A mother’s (MTHFR) gene polymorphisms, C677T and A1298C, may be implicated in the etiology of schizophrenia.
- Scientists have linked folate deficiency, reduction of Reelin mRNA, and the downregulation of Reelin during times of famine with the increased risk.
——————————————————————————————————- Every solution for even small pieces of the puzzle helps. —————————————————————————————————— Links
- “There is substantial sequence variation in mammalian mitochondrial DNA (mtDNA)9, and the high mutation rate is counteracted by different mechanisms that decrease maternal transmission of mutated mtDNA10,11, 12, 13.” http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12474.html
- Folate, Nutrition, and DNA Methylation Regulation overview by Dr. Patrick Stover, PhD, the Director of the Division of Nutritional Sciences at Cornell University http://www.human.cornell.edu/bio.cfm?netid=pjs13
- Vitamin deficiencies and mental health: How are they linked? by Drew Ramsey MD Assistant Clinical Professor of Psychiatry, Columbia University College of Physicians and Surgeons, and Philip Muskin MD Professor of Clinical Psychiatry, Columbia University College of Physicians and Surgeons
- Homocysteine and MTHFR Mutations, Circulation 2005
- L-methylfolate, methylcobalamin, N-acetylcysteine in the Treatment of Alzheimer’s Related Cognitive Decline, Primary Psychiatry | May 21, 2013
- Schizophrenia Linked to Abnormal Brain Waves “In the new study, which appears in the Oct. 16, 2013 issue of the journal Neuron, Tonegawa and colleagues at the RIKEN-MIT Center for Neural Circuit Genetics at MIT’s Picower Institute for Learning and Memory recorded the electrical activity of individual neurons in the hippocampus of these Calcineurin knockout mice as they ran along a track.” http://web.mit.edu/newsoffice/2013/schizophrenia-linked-to-abnormal-brain-waves-1016.html
- Mice modeling schizophrenia show key brain network in overdrive http://www.riken.jp/en/pr/press/2013/20131017_1/ (Note: calcineurin plays a crucial role in synaptic plasticity for learning and memory.)
- Calcineurin and EGR Family Transcription Factors – “New Schizophrenia-Associated Genes: Although pharmacological research in the past has indicated that the dysfunctioning of neurotransmitters such as dopamine and glutamates may be one of the causes of schizophrenia, we believe that the current research suggests that the calcineuron pathway is located at the confluence of the cascades of the two neurotransmitters (Fig. 2).” Laboratory for Molecular Psychiatry, RIKEN-MIT Neuroscience Research Center
- Sex effects on neurodevelopmental outcomes of innate immune activation during prenatal and and neonatal life. Aug. 6, 2012 Shadna A. Rana, Tooka Aavani, and Quentin J. Pittman, Hotchkiss Brain Institute, Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary Aug. 6, 2012 . .
- Lifetime prevalence of schizophrenia among individuals prenatally exposed to atomic bomb radiation in Nagasaki City. 1999 Imamura Y, Nakane Y, Ohta Y, Kondo H. Acta Psychiatr Scand. 1999 Nov;100(5):344-9.
- Bonding Hormone (Oxytocin) Improves Symptoms of Schizophrenia, 2010, by Jessica Ward Jones, MD, MPH. Research by Dr. David Feifel, Department of Psychiatry, University of California, San Diego Medical Center, San Diego, California. “by the end of the third week on the oxytocin nasal spray, the patients had on average an eight percent reduction of symptoms, including a decrease in symptoms of psychosis… as oxytocin has been shown to increase levels of trust, it may work by decreasing symptoms of paranoia.”
- Researchers uncover brain molecule regulating human emotion mood, Aug 7, 2013, Miyuki Kabayama, Kazuto Sakoori, Kazuyuki Yamada, Veravej G. Ornthanalai, Maya Ota, Naoko Morimura, Kei-ichi Katayama, Niall P. Murphy, and Jun Aruga. The Journal of Neuroscience, 2013. doi:10.1523/JNEUROSCI.5717-12.2013 “Monoamine oxidase A (MAO-A) is an enzyme that breaks down serotonin, norephinephrine and dopamine, neurotransmitters well-known for their influence on emotion and mood. Nicknamed the “warrior gene”, a variant of the MAOA gene has been associated with increased risk of violent and anti-social behavior…While evidence points to a link between MAO-A levels and various emotional patterns, however, the mechanism controlling MAO-A levels in the brain has remained unknown…Now, a research team headed by Jun Aruga at the RIKEN Brain Science Institute has shown for the first time that a ligase named Rines (RING finger-type E3 ubiquitin ligase) regulates these levels. Their research shows that mice without the Rines gene exhibit impaired stress responses and enhanced anxiety, controlled in part through the regulation of MAO-A levels.”
Gene Therapy: Can gene therapy change minds? Can we find a way to do this without invasive brain surgery? In the following interview with nature.com, Dr. Ki Goosens of the McGovern Institute for Brain Research at MIT tells Adam about the use of gene therapy to treat lifelong or debilitating conditions. Though typically considered for the treatment of cancerous cells, researchers are now proposing the use of gene therapy for debilitating brain-related disorders, such as severe post-traumatic stress disorder and schizophrenia. As with traditional gene therapy, these new applications proposed for the brain follow the same fundamental premise: scientists use an engineered virus — one that encloses a segment of DNA containing a beneficial gene — to infect cells with genes that have the potential to change an unhealthy cell into a healthy one. Join Adam as he learns about the process of and potential for gene therapy to cure conditions with a neurochemical basis http://www.youtube.com/watch?v=-m2x1KAzrMk
- Amygdala-Dependent Fear Is Regulated by Oprl1 in Mice and Humans with PTSD. http://www.researchgate.net/publication/237060671_Amygdala-Dependent_Fear_Is_Regulated_by_Oprl1_in_Mice_and_Humans_with_PTSD The amygdala-dependent molecular mechanisms driving the onset and persistence of posttraumatic stress disorder (PTSD) are poorly understood. Recent observational studies have suggested that opioid analgesia in the aftermath of trauma may decrease the development of PTSD. Using a mouse model of dysregulated fear, we found altered expression within the amygdala of the Oprl1 gene (opioid receptor-like 1), which encodes the amygdala nociceptin (NOP)/orphanin FQ receptor (NOP-R). Systemic and central amygdala infusion of SR-8993, a new highly selective NOP-R agonist, impaired fear memory consolidation. In humans, a single-nucleotide polymorphism (SNP) within OPRL1 is associated with a self-reported history of childhood trauma and PTSD symptoms (n = 1847) after a traumatic event. This SNP is also associated with physiological startle measures of fear discrimination and magnetic resonance imaging analysis of amygdala-insula functional connectivity. Together, these data suggest that Oprl1 is associated with amygdala function, fear processing, and PTSD symptoms. Further, our data suggest that activation of the Oprl1/NOP receptor may interfere with fear memory consolidation, with implications for prevention of PTSD after a traumatic event.
- (Note: Plasma homocysteine and liver choline metabolite levels are strongly dependent on the Mthfr genotype. Mthfr-compromised mice appear to be much more sensitive to changes of choline/betaine intake than do non-MTHFR compromised mice. On control diets, plasma homocysteine and liver choline metabolite levels were strongly dependent on the Mthfr genotype. Betaine supplementation decreased homocysteine in all three genotypes, restored liver betaine and phosphocholine pools, and prevented severe steatosis in Mthfr-deficient mice. – Zeisel FASEB J. 2003)
- I try on different theories about the origins of schizophrenia, for size. One theory is that the reason there is a downregulation of the fetal genes that encode channels, receptors, and transporters early in the pregnancy, is to protect the mother’s life. If the mother does not have enough of certain basic, vital nutrients such as folate or choline, whether due to her own genetic mutations, illness, or famine, fetal genes are downregulated through imprinting via long non-coding RNAs. This way, though the cost is high, the child’s needs do not damage the mother.
- “Transcriptomics studies have revealed the dynamic expression profile of several lncRNAs during the maturation of neuronal cell subtypes.29 Some studies revealed the presence of “brain-associated” lncRNAs that affect hippocampal development, oligodendrocyte myelination and aging in the brain.30 Thus, it is not surprising that the alteration of lncRNAs affects the basic functions of neuronal cells resulting in neurological and psychiatric disorders. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495748/
- “targeting lncRNAs can potentially restore the expression of a silenced gene which would be out of reach for conventional drugs.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3495748/
- Targeting long non-coding RNA to therapeutically upregulate gene expression, Nature Reviews Drug Discovery 12, 2013. Claes Wahlestedt obtained his M.D. and Ph.D. degrees from the University of Lund, Sweden, and currently holds a primary appointment as the Leonard M. Miller Professor at the University of Miami Miller School of Medicine, Florida http://www.nature.com/nrd/journal/v12/n6/full/nrd4018.html?WT.ec_id=NRD-201306
- “In particular defective placental development and physiology is a characteristic of perturbed imprinting. For example, absence of expression of a placenta-specific isoform of Igf2 (paternally expressed) causes impaired nutrient transport to the growing fetus (Sibley et al. 2004)… Although imprinting in the placenta provides a critical role in the control of resources at the interface between mother and fetus, perturbed imprinting in the embryo can influence its growth independent of an influence of the placenta.” ncbi.nlm.nih.gov/pmc/articles/PMC3119911“
- “Maternally expressed genes Ipl and p57Kip2 act to limit nutrient supply by the placenta.” Imprinted genes and mother-infant interaction
- RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders, PLoS One. 2011 Lin M, Pedrosa E, Shah A, Hrabovsky A, Maqbool S, Zheng D, Lachman HM.
- IMPRINTING: Methylators and Methylator Recruitors, lncRNAs
- Center for Psychiatric Genomics
- Note: Yes to neuro-systems biology.
- Expression of the placental transcriptome in maternal nutrient reduction in baboons is dependant on fetal sex, The Journal of Nutrition, Sept 18, 2013
- “Abnormalities in transcription factors, DNA methylation, and chromatin modifiers lie at the source…Dramatic changes in the expression of coding genes, long non-coding RNAs (lncRNAs), pseudogenes, and splice isoforms were seen during the transition from pluripotent stem cells to early differentiating neurons… A number of genes that undergo radical changes in expression during this transition include candidates for schizophrenia (SZ), bipolar disorder (BD) and autism spectrum disorders (ASD) that function as transcription factors and chromatin modifiers, such as POU3F2 and ZNF804A, and genes coding for cell adhesion proteins implicated in these conditions including NRXN1 and NLGN1. In addition, a number of novel lncRNAs were found to undergo dramatic changes in expression, one of which is HOTAIRM1, a regulator of severalHOXA genes during myelopoiesis. Finally, several lncRNAs that map near SNPs associated with SZ in genome wide association studies also increase during neuronal differentiation, suggesting that these novel transcripts may be abnormally regulated in a subgroup of patients.” Mingyan Lin (Department of Genetics, Albert Einstein College of Medicine), Erika Pedrosa, Abhishek Shah, Anastasia Hrabovsky, Shahina Maqbool, Deyou Zheng, Herbert M. Lachman. Editor Takeo Yoshikawa, Rikagaku Kenkyūsho Brain Science Institute, Japan September 7, 2011 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0023356
“Schizophrenia” is a collection of neurodevelopmental disorders…
“Recent evidence demonstrate that lncRNAs (long non-coding RNA) contribute to the complex biological system organization and gene regulatory networks of the central nervous system (CNS), affecting brain patterning, neural stem cell maintenance, neurogenesis and gliogenesis, stress responses, and synaptic and neural plasticity.” An Emerging Role for Long Non-Coding RNA Dysregulation in Neurological Disorders, Chiara Fenoglio, Elisa Ridolfi, Daniela Galimberti and Elio Scarpini, Int. Journal of Molecular Sciences, June, 2013. Allele-Biased Expression in Differentiating Human Neurons: Implications in Neuropsychiatric Disorders, PLOS one, Mingyan Lin, Anastasia Hrabovsky, Erika Pedrosa, Tao Wang, Deyou Zheng, and Herbert M. Lachman. (2012). doi:10.1371/journal.pone.0044017 “It has been suggested that most allele-biased expression is due to genetic factors , . This may well be the case for many of the genes in this study. However, several of the genes we validated, including CTNNA3 and the SZ candidate genes A2BP1 and ERBB4, showed random allele-biased expression suggesting an epigenetic phenomenon.” PLOS one 2013 “Distinguishing between genetic and epigenetic processes (both random monoallelic expression and imprinting) will require a much more extensive analysis using several different lines and multiple replicates. This is an important consideration in SZ and ASD because an epigenetic process accounting for allele-biased expression could have an impact on determining the efficacy of epigenetics-based treatment. ” PLOS one 2013 Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs, Epigenetics 2014; 9:0 – -1; PMID: 24149621; http://dx.doi.org/10.4161/epi.26700, Roberts TC, Morris KV, Weinberg MS. Department of Molecular and Experimental Medicine; The Scripps Research Institute; La Jolla, CA USA, Department of Physiology, Anatomy and Genetics; University of Oxford; Oxford, United Kingdom (via lncRNA Blog) Long non-coding RNA – Wikipedia MY QUESTION FOR RESEARCHERS
- Can and does vitamin D deficiency lead directly to long non-coding RNA dysregulation?
- Does vitamin deficiency lead to infection or increased autoimmunity that leads to long non-coding RNA dysregulation?