Dysregulation of MicroRNAs and Autism
A new study suggests that microRNAs (miRNAs)—a type of RNA (ribonucleic action), which is involved in protein synthesis—-may play a role in the development of autism. miRNAs are “abundant in the brain” and have a role in neurological diseases such as Tourette’s sydrome and Fragile X syndrome. Noting that autism is a “genetically complex disease,” researchers considered whether dysregulation of miRNA expression might play a role in autism. Specifically, the new study found that miRNAs can bind to longer RNA sequences and prevent them from making protein; according to Professor Kenneth S. Kosik, as quoted in a press release:
“It was of interest to find that various members of the microRNA family are frequently dysregulated in autism……This result points to a single control layer in the cell that can change in quite different ways with autism as the end result.”
The researchers found that genes which are “known genetic causes of autism”— Neurexin and SHANK3—were “among the predicted targets of dysregulated miRNAs.” Here’s the full abstract:
microRNAs (miRNAs) are ~21 nt transcripts capable of regulating the expression of many mRNAs and are abundant in the brain. miRNAs have a role in several complex diseases including cancer as well as some neurological diseases such as Tourette’s syndrome and Fragile x syndrome. As a genetically complex disease, dysregulation of miRNA expression might be a feature of autism spectrum disorders (ASDs). Using multiplex quantitative polymerase chain reaction (PCR), we compared the expression of 466 human miRNAs from postmortem cerebellar cortex tissue of individuals with ASD (n = 13) and a control set of non-autistic cerebellar samples (n = 13). While most miRNAs levels showed little variation across all samples suggesting that autism does not induce global dysfunction of miRNA expression, some miRNAs among the autistic samples were expressed at significantly different levels compared to the mean control value. Twenty-eight miRNAs were expressed at significantly different levels compared to the non-autism control set in at least one of the autism samples. To validate the finding, we reversed the analysis and compared each non-autism control to a single mean value for each miRNA across all autism cases. In this analysis, the number of dysregulated miRNAs fell from 28 to 9 miRNAs. Among the predicted targets of dysregulated miRNAs are genes that are known genetic causes of autism such Neurexin and SHANK3. This study finds that altered miRNA expression levels are observed in postmortem cerebellar cortex from autism patients, a finding which suggests that dysregulation of miRNAs may contribute to autism spectrum phenotype.
The study, Heterogeneous dysregulation of microRNAs across the autism spectrum, was published June 19 in Neurogenetics by researchers from the Neuroscience Research Institute, and Department of Molecular Cellular and Developmental Biology, University of California Santa Barbara.
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15 opinions for Dysregulation of MicroRNAs and Autism
daedalus2u
Jun 26, 2008 at 4:30 pm
It is unfortunate that they use the term “dysregulation” when all they found were differences. Whether those differences are actually a sign of or caused by dysregulation is unknown.
“There is such a broad interest in autism,” Kosik said. “This is the first work in this area.”
I guess that is why he felt the need to issue a press release, to puff up the “impact” of his miRNA research. Just trying to tap into the research money available in autism.
Emily
Jun 26, 2008 at 7:57 pm
miRNAs are hot stuff right now in just about any area considered “disorder.”
Kristina Chew, PhD
Jun 26, 2008 at 8:53 pm
Why, if I may ask?
daedalus2u
Jun 27, 2008 at 7:57 am
miRNAs are small enough that small labs can sequence and identify them, they are likely a lot of them, probably more than the thousand or so mentioned in the article perhaps many times more. They are likely to be different in different cells, in different tissue compartments, at different stages of development, in different normal and disordered states. There is a lot of research space for people to explore in. Who ever gets there first will be the “expert” in a new area.
Because they are small, there is a possibility that they can be delivered, perhaps via a viral vector or some other mechanism and be used in treatments. It is clear they have to be important, but whether they can be used as a treatment is completely unknown.
My own thought is that the regulation of DNA expression is too complicated and intricate to be able to “hack” into it with something so crude. It would be like finding out your computer runs on electricity, and then trying to “hack” into it and reprogram it using a car battery and jumper cables, while it is running, without having a schematic or the source code, in the dark, working by touch while wearing boxing gloves.
I wouldn’t want to discourage anyone from doing this kind of research (or any kind of research), but to expect treatments out of it in the near term (i.e. in less than 20 years) is naïve (I think, but I could easily be wrong). The complexity of systems like this don’t scale linearly, they scales exponentially. Adding an extra thousand gene control factors (or 10,000?) multiplies the complexity of the gene network being controlled.
It does take a certain type of confidence and hubris to boldly propose hacking into something so complicated. The problem (and I see it as a big problem) is who gets the research funding? The researcher who see the complexity and how to make incremental progress, or the researcher who is blind to the complexity and promises a “cure”?
RAJ
Jun 27, 2008 at 10:08 am
“Among the predicted targets of dysregulated miRNAs are genes that are known genetic causes of autism such Neurexin and SHANK3″.
Nonsense, they are not known genetic causes of autism. This a leap of faith by the authors because both Neurexins and Shank3 anomolies are reported in genetic syndromes whose phenotype is mental retardation with a subgroup who have enough nonspecific isolated symptoms (eg autistic-type symptoms) to qualify for an ASD diagnosis.
The association with neurexins was made by the Autism Genome Consortium and consisted of exactly two case who were sisters and were also mentally retarded.
http://www.ncbi.nlm.nih.gov/pubmed/17322880?
Shank3 abnormalites are also reported in neurodevelopmental disorders with or without autistic features:
http://www.ncbi.nlm.nih.gov/pubmed/16284256
Kristina Chew, PhD
Jun 27, 2008 at 10:39 am
@daedalus2u,
you noted that “Just trying to tap into the research money available in autism”—–I read about a study involving myelin research and Alzheimers, and autism, some time ago and the inclusion of autism seemed somewhat tangential. I’ve been wondering if more and other researchers might seek to do/add autism as a research interest due to funding available?
Regan
Jun 27, 2008 at 3:25 pm
I don’t have a problem with basic research in this area, or even if there are some deadends. If we knew all the answers beforehand one wouldn’t need to bother with the research.
FWIW–Daniel H. Geschwind is listed as a co-author on this paper, so I don’t think that they are jumping into this completely unawares for the grant money.
daedalus2u
Jun 27, 2008 at 10:51 pm
I really think there should be much more interdisciplinary work in the various neurological disorders. I think there are far more similarities than differences. They appear different at the macroscopic level, but when you look at the microscopic level there are a number of commonalities.
For example reduced metabolic capacity is involved in essentially all neurodegenerative diseases, including Alzheimer’s, Parkinson’s, Lewy body neuropathies, vascular dementia, MS, ALS, neuroinflammation, and also in autism (autism is not a neurodegenerative disorder, but it does exhibit reduced brain metabolism).
If metabolic capacity is reduced, how many pathways are affected? Is it a few pathways going bad? That does not appear to be the case because the reduction in metabolic capacity exceeds that which could occur from only a few pathways. Metabolic capacity is regulated in each cell independently (but there is signaling between cells). Is the reduced metabolic capacity from many pathways “going bad” in each nerve cell independently? Or is it the global regulation of metabolic capacity that has “gone bad”.
I think it is the latter, what I call good regulation around a bad setpoint. Under this hypothesis, the regulation of metabolism is still going on, that is the control pathways are still working the way they are “supposed to”, just they are regulating to a bad setpoint. If your thermostat gets set to 95, you can’t “fix” it by buying window air conditioning units. You have to “fix” it by lowering the setpoint.
If the ATP setpoint in the brain is low, the only way to fix it is by raising it. NO is what sets the ATP setpoint by the interaction of ATP and NO on soluble guanylyl cyclase. Low NO lowers the ATP setpoint and lowers metabolic capacity. I think low NO causes all of the neurodegenerative diseases. Low NO is the final common pathway.
MikeO'Neill
Jun 28, 2008 at 1:14 am
http://www.livescience.com/health/060817_brain_boot.html
Your Brain Boots Up Like a Computer
Our pediatrician is recommending hyperbarics (and is soon to be involved in a hyperbarics/asd study (first double blind)) One theory is adding the extra 02 gets pushed to the brain where pathways may be blocked.
Im going to show my ignorance - if someone was suffering from low NO - could the extra 02 in the brain mix and lower it more??
Thanks in advance - MO
Kristina Chew, PhD
Jun 28, 2008 at 1:28 am
@daedalus2u,
now you’ve got me thinking about this analogy—” If your thermostat gets set to 95, you can’t ‘fix’ it by buying window air conditioning units. You have to ‘fix’ it by lowering the setpoint.”
@Mike, hope you don’t mind if I ask—why in particular is your pediatrician recommending hyperbarics, for autism and/or PDD and/or mito? regards—
daedalus2u
Jun 28, 2008 at 8:34 am
Hyperbaric O2 is extremely dangerous. It is one of the things that will very reliably induce seizures in healthy adults. Pure O2 (at 1 atmosphere) will kill a mouse in a few days.
O2 is not actively transported. O2 passively diffuses in the lung into red blood cells which are transported by the blood. In the peripheral tissues that O2 then passively diffuses out of the blood cells into the tissues requiring O2. There is no active transport at all. The O2 concentration in the peripheral tissues are the lowest O2 concentration in the body, they have to if O2 is going to diffuse there and be consumed. There are no “pathways” that carry O2 which might be blocked. O2 is freely diffusible in all tissue compartments except for crystalline bone. Cell membranes are completely permeable to O2 as are all tissues.
If there is a problem of not enough O2, the “problem” is due to insufficient vascularization due to inappropriate regulation of vascularization. If regulation of vascularization were to “go bad”, it would affect every tissue that is vascularized (that would be every tissue). That bad regulation is actually good regulation around a bad setpoint.
What is hyperbaric O2 doing to people with autism? No one knows. We do know that autism is not caused by being in an environment with not enough O2. There has been no theoretical explanation of any physiology behind how not enough O2 would cause autism, and how more O2 would fix it.
Air is ~21% O2. Pure O2 by mask is 100% O2, or 5 times higher. Blood can’t carry very much more O2 in hemoglobin because the hemoglobin saturates at near atmospheric levels. The level in plasma varies with the O2 partial pressure, but that quantity is small compared to the amount in hemoglobin. There have been some posts on hyperbaric O2 on the Autism Hub, I think Prometheus did one.
There have been no studies of what hyperbaric O2 does to children. Such studies would be unethical in normal children. I think they would be unethical in children affected by disorders where there is no known or even plausible causal mechanism related to low O2. Disorders with no plausible mechanisms related to low O2 would include autism.
Autism is characterized by oxidative stress. Hyperbaric O2 will increase oxidative stress. That is what causes the seizures of hyperbaric O2. Maybe inducing seizures will help people with autism. Electroconvulsive therapy is used to treat a number of disorders by inducing seizures. ECT is a much safer way of inducing seizures than is hyperbaric O2. Why you would impose a treatment that would increase oxidative stress in a disorder already characterized by oxidative stress is not clear to me.
If my child’s pediatrician recommended hyperbaric O2 for something for which there was no underlying theory, no underlying clinical studies and no plausible mechanism, and was setting up a business to profit from it by selling a “treatment” with no actual clinical indication (but which can harm children), I would take that as a sure sign the pediatrician was not practicing evidence based medicine but quackery and would find a different pediatrician ASAP.
Regarding your question, more O2 certainly could lower NO levels. That is what oxidative stress does, it lowers NO levels. I think that is the mechanism for seizures, oxidative stress lowers NO levels so much that a seizure is induced. I think that one of the roles of seizures is to “prune” the number of neurons in the brain to match the metabolic load of the brain with the supply of nutrients by the vasculature. If there isn’t “enough” vasculature to supply that brain region, metabolic stress leads to oxidative stress, low NO and a seizure. That seizure then “prunes” some neurons to reduce metabolic load in that seizing volume.
Mike O'Neill
Jul 1, 2008 at 5:23 pm
Ok, I hope you are still there. busy weekend. I had to research to figure out what I thought I was talking about. Oxidative stress is what I am concerned about so thanks for the response. Thats a scarry thought on seizures. Was this your own conjecture and are their studies? My understanding of vascularization is that it is regulated by NO. I am also concerned that repeated dives could lower the set point, just as when athleets train at high altitudes to improve o2 absorption (hemoglobin production?).
I have my concersn about HBOT however, I dont think wholesale condemnation of our holistic pediatrician is called for. We have had great success in improving my sons quality of life and have nothing from the establishment other than ABA. I sent him to the neurologist today just to try to make use of the insurance and rule out all the other possible x linked disorders. His therapists have also acknowledged his improvement. I had planned the website thaddeusrex.net to document his diagnosis, treatments and progress and as an awareness site but I have been too busy. (in fact I am at work now- lol)
@Kristina The recommendation for HBOT is generic as he is seing alot of improvement with patients in that area. These are mild/portable hbot chambers with o2 concentrators (up tp 95% pure 02 and 5%”air”) and dive to the equivalent to 25 feet which is the last stop you would make on a dive to decompress. There should be no concern of the “bends” and these can be purchased for home use without prescription.
Why?
It was basically explained to me as more o2 to the brain.
Forgive me for the rather lengthy post from http://www.hbotreatment.com/Autism.htm and there is more info there on how HBOT is thought to work.
In one study, involving brain functionality and recovery for children with chemical exposures exhibiting PDD disorders, hyperbaric oxygen therapy was found to be remarkably effective. Treatments consisted of 10 sessions in a hyperbaric chamber at 1.3 ATA, for one hour per day, five consecutive days for two weeks. To increase validity to the study results, SPECT scans of each patient’s brain were taken before and after the hyperbaric treatments to quantify physical changes to the brain tissue. The SPECT scan showed an increase to blood flow and oxygen to the temporal lobe. SPECT scans of patients taken before hyperbaric treatments showed a significant amount of dormant activity while scans taken of patient brains after hyperbaric indicated an increase in brain activity and blood flow. After hyperbaric therapy, dormant brain regions were replaced with greater functioning tissues and represented a scan more similar to a healthy individual. Some theories suggest that the brain in some persons with Autism, as well as Cerebral Palsy and other neurological disorders, is lacking oxygen and in a dormant, or sleeping state due to lack of blood flow. Hyperbaric forces oxygen into tissues throughout the body including brain tissues and fluid, resulting in a re-awakening of dormant areas of the brain. Other theories state that excessive swelling in the brain results in a lack of oxygen causing cerebral impairment that can cause behavioral problems, confusion, etc. Oxygen is forced into these damaged areas, through the pressurization of hyperbaric, which alleviates brain swelling by constricting blood vessels. In addition, hyperbaric is thought to provide an optimal environment to assist in the regeneration of brain tissue.
daedalus2u
Jul 1, 2008 at 9:58 pm
The “theories” you mention have no documented basis in physiology. They are simply made-up ideas to try and extract money from gullible parents.
There is no brain damage observed in autism. There is inflammation and oxidative stress, something I would expect to get worse with hyperbaric oxygen.
Since this is a “study”, I assume that it is paid for by those funding the research and not the subjects? I assume that this is a double-blind placebo controlled study? The placebo effect is quite strong. The placebo effect alone might be what is causing any “improvement” said to be observed.
Here is a study on HBO2 causing seizures in rats.
http://jap.physiology.org/cgi/content/full/91/3/1327
Why are they doing SPECT other than because they can and can charge for it? What differential treatment will the differential diagnosis of a SPECT scan result in? If there is no differential treatment, the test has no clinical utility. If there is no clinical utility why is it being done?
If there is excessive swelling of the brain, hyperbaric O2 is not the treatment. Anyone with actual excessive swelling of the brain should get the appropriate treatment immediately.
Are those portable hyperbaric units rated for O2? Oxygen is extremely dangerous. 95% O2 is extremely dangerous.
http://www.eiga.be/pdf/Info_15_08.pdf
Before I would let my child into an enriched O2 atmosphere I would want to know that the manufacturer of the equipment designed it and rated it for O2 service at the pressure it is being used at. Virtually everything will burn vigorously in pure O2 including human flesh.
Kristina Chew, PhD
Jul 1, 2008 at 10:42 pm
@Mike O’Neill,
Hope you continue to see improvements in your son—–we have tried many things over the years, but have returned again and again to ABA and teaching and school. The biomedical treatments seemed to offer a lot of hope but the results were always short-lived, for us, at least, and I’ve become a bit more wary of hearing of the latest treatments and their results over time. But really hope things continue to get better—- very best.
MikeO'Neill
Jul 1, 2008 at 11:40 pm
My wife will be attending an autism conference in orlando next week. On thursday there is a talk on oxidative stress and a talk on HBOT (2008 ASA National Conference). We are newbies as Thad is 3 . The pediatrician is pretty straight - his 5/6 year old was a special needs with a brain hemorrhage at birth. He left aids work to do pediatrics. We have discovered a phenol transfer issue (he cant break down b6-p5p (which sent him into classical autism after 2 weeks at 25- 50 mg)) Responds phenomenally to epsom salts. Has low creatine , triple the amount of testosterone for a teenager, and had a large colon yeast infection. Treating these with fluconcozole, l-carnitine, bioton, b2, and methyl b12 has made a marked improvement. (also on a gfcf soy free diet) He has apraxia, and was unable to say mom, or bye (m or b) even after 12 months of speach and 6 months of ABA. After 3 weeks on the above treatment he is breaking out with “bye bye mickey mouse”. I certainly understand the one step forward 6 steps back. We look so hard for the smallest sign of improvement as each day can be a struggle with the stares from strangers, tantrums, not eating, dilated pupils etc. I have made a commitment to do everything in my power to help him, just as most parents have. When I feel discouraged I re double my efforts.
@Daedulas2, thanks for the info - I am definitely going to review the audio cd from the upcoming conference. I wish I could go as well - am trying to bring wife up to speed on some things.
-Peace
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