 | Understanding the formation, function and manipulation of microRNA (miRNA) is a new and exciting area of genetic research. MicroRNA are implicated in diseases like cancer, multiple sclerosis, Parkinson's disease and Alzheimer's disease (Li 2012). They have also been studied for their role in developmental and cognitive function in Down syndrome. I'll explain here some basic principles of how RNA functions to make protein from DNA and how microRNA function differently in Down syndrome as well as some tools that are potentially helpful to normalize their function. |
Let's back up. Many of you reading this may not even know what RNA is, let alone microRNA. Take a look at this video below to get a basic understanding of what RNA is and does.
You can see here that RNA is a copy of DNA that carries the instructions from DNA to make proteins. It should go without saying that this process is far more complicated than you see here. It involves hundreds of steps, each requiring various enzymes, compounds, hormones, and regulators that goes beyond what most doctors even learn in medical school. It most likely involves more steps than is even known by top researchers today. In fact, the science behind microRNA is in it's infancy as it was discovered only 15 years ago.
MicroRNA are one type of RNA that are small segments of RNA not required in the process of making proteins, like messenger RNA, ribosomal RNA or transfer RNA that you learned about in the above video. They function to regulate or silence messenger RNA before it can even make a protein. There are several other forms of gene regulation including DNA methylation that occur before this step.
If you want to learn more indepth information about microRNA you can watch the video below. However, for the purpose of this blog post simply knowing that they function to silence gene expression is key.
MicroRNA are one type of RNA that are small segments of RNA not required in the process of making proteins, like messenger RNA, ribosomal RNA or transfer RNA that you learned about in the above video. They function to regulate or silence messenger RNA before it can even make a protein. There are several other forms of gene regulation including DNA methylation that occur before this step.
If you want to learn more indepth information about microRNA you can watch the video below. However, for the purpose of this blog post simply knowing that they function to silence gene expression is key.
As mentioned ealier, microRNA have been studied in Down syndrome to better understand if they contribute to the phenotype and intellectual disability of Down syndrome. Currently, five microRNA have been found to be overexpressed in individuals with Down syndrome. Two of these five microRNA are also triplicated in the brain tissue of Ts65Dn mice (mice genetically modified to replicate the Down syndrome model). These two microRNA are miR-155 and miR-802 (Bofill-De Ros 2015). These researchers from Barcelona, Spain studied these two microRNA by exposing the hippocampal cells in Ts65Dn mice, where the microRNA are overexpressed, to an agent that lowers levels of microRNA called a lentiviral sponge. By doing this they were able to determine which genes were regulated by miR-155 and miR-802. They discovered a new set of genes, not on chromosome 21, that are downregulated and potentially contribute to impaired neuronal function in those with Down syndrome. Researchers from the University of Buffalo in New York found that miR-155 controls genes in the nucleus that are involved in mitochondrial biogenesis, the formation of new mitochondria. These genes are called TFAM (mitochondrial transcription factor A). There was a negative association between miR-155 and TFAM, meaning the more miR155 there was the less TFAM they detected (Quiñones -Lombraña 2015).
An additional bit of information I would like to add to this is about the role that active thyroid hormone (T3) has on the function if microRNA. Several studies exist that connect T3 to the regulation of microRNA. T3 was found to regulate microRNA in renal cancer cells (Boguslawska 2014). Thyroid control of microRNA was also studied in mice. "We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls." (Hongyan 2010) T3 has also been shown to regulate the levels of microRNA in human skeletal muscles (Visser 2009) and in heart tissue (Janssen 2014). Is it possible that miR-155 is also regulated by T3? We don't know, because it hasn't been studied. Given the very prevalent hypothyroid symptoms seen in patients with Down syndrome and the higher rate of hypothyroidism than is reported when we look at serum free T3 levels, I believe it's possible that thyroid hormone is, once again, involved in this imbalanced process of genetic control.
You can see by the dates of the research cited here that this information is all very new and my theory about thyroid hormone is just that, a theory. The key question, as always, is how we can apply this to help those with Down syndrome now?
Natural agents have been studied for their effect on microRNA in the context of cancer treatment. Some of those agents include curcumin, isoflavone, I3C (indole-3-carbinol), DIM (dindolylmethane), EGCG and resveratrol (Yiwei 2013).
Resveratrol stands out due to the studies that have specifically tested it against miR-155. Again, these are within the context of cancer, but it was shown to downregulate miR-155. The means by which this occured was the upregulation of other microRNA, namely miR-663 (Tili 2010, Latruffe 2015). Whether this is the means by which we want to lower miR-155 levels in Down syndrome us unknown.
Resveratrol is a compound found in high concentration in grape skin and Japanese knotweed. It is categorized as an antioxidant and an anti-imflammatory. It has not been studied specifically in the Down syndrome model. It has, however, been studied for it's impact on Alzheimer's disease, which is found in 100% of patients with Down syndrome as early as 40 years old (Rafii 2014). Teng Ma, et al discuss the latest research supporting resveratrol for it's neuroprotective effects and it's therapeutic potential in Alzheimer's disease. They concluded that, "For the antioxidative and anti-inflammatory functions, resveratrol truly represents the beneficial effects on AD." (Teng Ma 2014).
Dosage is important and clinical trials to determine safe and effective doses are just now coming out. In October of 2015 it was reported that doses as high as 1,000 mg twice a day in adults resulted in less of a decline in Aβ40 than in those who were taking placebo (Turner 2015). A decline in Aβ40 indicates progression of the disease (Honig 2014). It was generally well-tolerated at these very high doses despite some reports of nausea, diarrhea and weight loss. Levels of resveratrol were also tested in the cerebral spinal fluid (CSF) of patients taking it and it was found to be present, indicating it's ability to cross the blood brain barrier. In 2011 doses as high as 5 g/day in adults was reported to safe and "reasonably" well-tolerated (Patel 2011). Mukherjee, et al state in their review, "Thus, at lower dose, resveratrol can be very useful in maintaining the human health whereas at higher dose, resveratrol has pro-apoptotic actions on healthy cells, but can kill tumor cells." (Mukherjee 2010). Many compounds, natural and synthetic have different effects at low doses versus higher doses.
An example of the sheer number of doses of resveratrol that are being tested can be seen in Singh's review of resveratrol's effect on the brain after stroke. More than twelve different doses were reported as having been tested, ranging from 1 mg/kg to 100 mg/kg (Singh 2013). Dr. Jill Crandall states in her report in 2013, "Doses used in animal (5–500 mg/kg/day) and human studies (5–5,000 mg/day) have varied widely, and not enough is known about the dose-response relationship." (Crandall 2013).
Many parents who use resveratrol are using 0.5-2 mg/kg per day, but this dose has not been tested to be effective at reducing miR-155 nor has it been proven to be effective at impacting cognitive impairment in Down syndrome.
So where does that leave us? Many parents are using a lot of supplements in very young children with Down syndrome and safety is of utmost importance. I do support parents and caregivers using resveratrol in their loved ones with Down syndrome, however, I can't make a recommendation about dosage that has been proven to be effective in studies or in clinical trials.
At this time no therapy has been developed to treat the over-expression of miR-155 and miR-802 for individuals with Down syndrome. However, researchers are working diligently to discover ways to specifically control miR-155 and other microRNA. One means that is being studied is lentiviral sponges (Ebert 2010), as mentioned earlier. This research is in it's infancy and clinical trials are many years away. This research is on my radar and I will continue to report new doscoveries.
I hope this explanation has been helpful to parents and caregivers who are trying to understand these very complicated biochemical processes that are being studied in order to help individuals with Down syndrome.
Edited March, 2016:
New studies are emerging supporting the benefits of resveratrol in the Down syndrome mouse model (Valenti 2016). Valenti, et al showed that resveratrol not only increased neural progenitor cells, it also increased generation of new mitochondria.
An additional bit of information I would like to add to this is about the role that active thyroid hormone (T3) has on the function if microRNA. Several studies exist that connect T3 to the regulation of microRNA. T3 was found to regulate microRNA in renal cancer cells (Boguslawska 2014). Thyroid control of microRNA was also studied in mice. "We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls." (Hongyan 2010) T3 has also been shown to regulate the levels of microRNA in human skeletal muscles (Visser 2009) and in heart tissue (Janssen 2014). Is it possible that miR-155 is also regulated by T3? We don't know, because it hasn't been studied. Given the very prevalent hypothyroid symptoms seen in patients with Down syndrome and the higher rate of hypothyroidism than is reported when we look at serum free T3 levels, I believe it's possible that thyroid hormone is, once again, involved in this imbalanced process of genetic control.
You can see by the dates of the research cited here that this information is all very new and my theory about thyroid hormone is just that, a theory. The key question, as always, is how we can apply this to help those with Down syndrome now?
Natural agents have been studied for their effect on microRNA in the context of cancer treatment. Some of those agents include curcumin, isoflavone, I3C (indole-3-carbinol), DIM (dindolylmethane), EGCG and resveratrol (Yiwei 2013).
Resveratrol stands out due to the studies that have specifically tested it against miR-155. Again, these are within the context of cancer, but it was shown to downregulate miR-155. The means by which this occured was the upregulation of other microRNA, namely miR-663 (Tili 2010, Latruffe 2015). Whether this is the means by which we want to lower miR-155 levels in Down syndrome us unknown.
Resveratrol is a compound found in high concentration in grape skin and Japanese knotweed. It is categorized as an antioxidant and an anti-imflammatory. It has not been studied specifically in the Down syndrome model. It has, however, been studied for it's impact on Alzheimer's disease, which is found in 100% of patients with Down syndrome as early as 40 years old (Rafii 2014). Teng Ma, et al discuss the latest research supporting resveratrol for it's neuroprotective effects and it's therapeutic potential in Alzheimer's disease. They concluded that, "For the antioxidative and anti-inflammatory functions, resveratrol truly represents the beneficial effects on AD." (Teng Ma 2014).
Dosage is important and clinical trials to determine safe and effective doses are just now coming out. In October of 2015 it was reported that doses as high as 1,000 mg twice a day in adults resulted in less of a decline in Aβ40 than in those who were taking placebo (Turner 2015). A decline in Aβ40 indicates progression of the disease (Honig 2014). It was generally well-tolerated at these very high doses despite some reports of nausea, diarrhea and weight loss. Levels of resveratrol were also tested in the cerebral spinal fluid (CSF) of patients taking it and it was found to be present, indicating it's ability to cross the blood brain barrier. In 2011 doses as high as 5 g/day in adults was reported to safe and "reasonably" well-tolerated (Patel 2011). Mukherjee, et al state in their review, "Thus, at lower dose, resveratrol can be very useful in maintaining the human health whereas at higher dose, resveratrol has pro-apoptotic actions on healthy cells, but can kill tumor cells." (Mukherjee 2010). Many compounds, natural and synthetic have different effects at low doses versus higher doses.
An example of the sheer number of doses of resveratrol that are being tested can be seen in Singh's review of resveratrol's effect on the brain after stroke. More than twelve different doses were reported as having been tested, ranging from 1 mg/kg to 100 mg/kg (Singh 2013). Dr. Jill Crandall states in her report in 2013, "Doses used in animal (5–500 mg/kg/day) and human studies (5–5,000 mg/day) have varied widely, and not enough is known about the dose-response relationship." (Crandall 2013).
Many parents who use resveratrol are using 0.5-2 mg/kg per day, but this dose has not been tested to be effective at reducing miR-155 nor has it been proven to be effective at impacting cognitive impairment in Down syndrome.
So where does that leave us? Many parents are using a lot of supplements in very young children with Down syndrome and safety is of utmost importance. I do support parents and caregivers using resveratrol in their loved ones with Down syndrome, however, I can't make a recommendation about dosage that has been proven to be effective in studies or in clinical trials.
At this time no therapy has been developed to treat the over-expression of miR-155 and miR-802 for individuals with Down syndrome. However, researchers are working diligently to discover ways to specifically control miR-155 and other microRNA. One means that is being studied is lentiviral sponges (Ebert 2010), as mentioned earlier. This research is in it's infancy and clinical trials are many years away. This research is on my radar and I will continue to report new doscoveries.
I hope this explanation has been helpful to parents and caregivers who are trying to understand these very complicated biochemical processes that are being studied in order to help individuals with Down syndrome.
Edited March, 2016:
New studies are emerging supporting the benefits of resveratrol in the Down syndrome mouse model (Valenti 2016). Valenti, et al showed that resveratrol not only increased neural progenitor cells, it also increased generation of new mitochondria.
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