Archive for March, 2013

Copper is an important trace element and plays a vital role to our overall health. It may play an even bigger role in maintaining our neurological health. Copper is found in every single cell of our bodies and plays a role in respiration, neurotransmitter biosynthesis, and connective tissue strength. Too little copper leads to incomplete development however, excess copper can have negative health consequences such as mitochondrial and DNA damage (http://ajcn.nutrition.org/content/88/3/855S.full).

Copper is found in abundance in the basal ganglia. Remember from previous articles this is where the GABA deficiency lies in HD and leads to chorea. It is interesting to note that copper is a “potent inhibitor of GABA-evoked responses in rat Purkinje cells” (http://ajcn.nutrition.org/content/88/3/855S.full). My question then is excess copper a cause for the chorea seen in HD?

Another interesting note is that glutathione may bond to copper to excrete it. If you haven’t read my previous post regarding oxidative stress and HD I recommend you read it now, https://geneticpotential.wordpress.com/2013/03/04/circadian-melotonin-and-huntingtons-disease/. Glutathione depletion may lead to excess copper, which may lead to an inhibition of GABA, which may lead to chorea. The depletion of glutathione may actually be the cause of numerous psychological disorders as excess oxidative stress is a major player in behavioral issues. I wrote about fixing glutathione levels here, https://geneticpotential.wordpress.com/2013/03/05/n-acetylcysteine-and-the-fight-against-oxidative-stress-in-huntingtons-disease/.

Copper and zinc need to be in balance. The proper ratio is .7 copper:1 zinc. Excess copper and deficient zinc are the norms in ADHD, depression, autism, and PMS. Research has used zinc finger ions to reduce the chromosomal expression of the Huntington gene. In the mouse model they experimented with there was a delay in the onset of symptoms (http://www.sciencedaily.com/releases/2012/10/121010131358.htm). Copper and zinc balance seems to be an important factor in the development of the disease so how do we manage our balance?

There are blood tests that can be run to check the levels of both. It is also important to check the levels of vitamin B1, B3, B6, folate, inositol, and choline as they play a role in reducing copper. Stress depletes zinc levels. In fact zinc deficiency causes a reduction in glutathine (http://www.sciencedirect.com/science/article/pii/S0009279703000875). Less glutathione can leave excess copper as it plays a role in removing copper from the system throwing our balance of the two way off.

Foods such as nuts, beans, seeds, grains, and chocolate all increase copper levels. These foods would be best avoided by those with the Huntington gene. Also, certain IUDs and birth control pills contain copper as well as some multivitamins. All of which should be avoided if you have the Huntington gene. A blood test to determine an imbalance and maintaining the proper .7:1 copper:zinc balance may be another way that the onset of symptoms can be delayed in this disease.

One important, and often overlooked, aspect of health that plays a role in almost every disease is inflammation. Neurodegenerative disorders such as Alzheimer’s and Parkinson’s have strong ties to inflammation. This is also true of depression, anger, anxiety, and other behavioral issues. During the inflammation process, protein messangers called cytokines are released. These cytokines can cross the blood brain barrier and suppress cell functioning in the brain. This is where the neurodegeneration and behavioral problems can be seen.

So how does this relate to Huntington’s Disease (HD). HD is a neurodegenerative disease that is accompanied by psychological symptoms so why would we not think that inflammation plays a key role? One marker studies look at for inflammatory damage is an increase in peripheral type benzodiazepine binding sites (PTBBS). PTBBS are found in higher numbers when neuronal damage is present (http://brain.oxfordjournals.org/content/123/11/2321.short). High levels of PTBBS were found in the putamen and moderate levels were found in the frontal cortex of patients with HD (http://www.sciencedirect.com/science/article/pii/S0304394097009671). This is what is seen in patients with other forms of neurodegeneration.

Two specific inflammatory markers I want to discuss are IL-6 and TNF-alpha. These two inflammatory cytokines are found in increased levels in the striatum, a part of the brain seriously affected in HD. Research has also shown that this increase in IL-6 leads to immune cell hyperactivity in the cells containing the abnormal HUntington protein. The exciting part is that these markers can be found in patients with the HD gene years before any symptoms begin (http://hdresearch.ucl.ac.uk/our-results/inflammation/). This may lead to other treatments that can help delay the age of onset, but also may give us a look into the pathology of the disease.

Perhaps the body produces an inflammation response to the abnormal Huntington protein. Inflammation does not do its damage immediately. It takes time for it to take its toll. Perhaps it is this continued inflammation response that damages neurons and leads to the onset of symptoms? The other interesting concept is the role of stress and our neurotransmitter GABA.

GABA is like our body’s valium. During high stress times we release GABA to cal ourselves down. Over time GABA can become depleted and this can lead to an imbalance. Chorea is another symtpom of HD and it is caused by a decrease in GABA in the basal ganglia. This leads to a lack of inhibition for dopamine and excessive movement. This is one area I am going to look into more. In the meantime manage your stress, with or without a HD diagnosis!

For those that have not seen the first article I posted regarding methylation here it is: https://geneticpotential.wordpress.com/2013/03/12/dna-methylation-and-gene-expression/.

Interesting studies have come out within the last couple of months regarding methylation and Huntington’s Disease. One of which originated out of my home state of Massachusetts at MIT. The researchers found that cells with normal Huntington proteins had dramatically different patterns of methylation then the cells with the abnormal protein. Some gained methyl groups, while others lost them (http://www.medicalnewstoday.com/articles/255191.php).
If you remember from my previous article, methylation is a way for our body to turn off specific genes. If we can figure out how to normalize methylation, or at least imprve it we should be able to increase the age of onset for the disease. Ultimately this may even lead to a cure.
Another interesting fact from the study that I mentioned earlier was that the researchers determined that the abnormal protein specifically targets genes involved with brain function. The location also happens to be in the regions of the genome that controls the switching on and off of neighboring genes. Genes that are responsible for growth and function of the brain. If this is true then HD is not only a neurodegerative disorder, but it also blocks the brain’s ability to grow and function while destroying it. My question is still, why does this not happen earlier in life? How can someone live symptom free for 35-50 years?
This may be because methylation is not a fixed process. In fact it can change throughout the life cycle. Perhaps there is a normal methylation process early on in the disease and then something triggers a change which leads to a decrease in methyl groups and an increase in the expression of the abnormal Huntington protein.
In previous articles I also described how glutathione gets depleted and there is an increase in reactive oxygen species (ROS) within the cells. The depleted glutathione may set the stage for altered methylation. The methyl donor, methionine becomes depleted as glutathione becomes depleted (http://www.sciencedirect.com/science/article/pii/S0304383597003005). Less methionine equals less methylation. Oxidative damage takes time to leave its mark and just maybe one of those marks is decreasing methylation. Ths would allow for an increase in the expression of the abnormal Huntington gene.

Where I stand right now is if we can catch the disease early on with genetic testing we can monitor intracellular glutathione levels and make sure they stay at normal levels. At the same time we can use a highly nutritious diet and possably some supplementation to make sure that all the nutrients required for methylation stay up. It does not look like there is a problem with the methyltetrahydrofolate reductase (MTHFR) gene. A gene responsible for folate metabolism (http://www.jnrbm.com/content/4/1/12).

http://robbwolf.com/2013/03/13/understanding-combating-oxidative-stress-huntingtons-disease/

For those of you who have not read my article concerning epigenetics, I encourage you to read it here, https://geneticpotential.wordpress.com/2013/02/27/epigenetics-understanding-gene-expression/.

 

DNA methylation in a nutshell is the addition of a methyl group to DNA nucleotides.  The methylation process is a way that our body turns off certain genes.    Not all genes are turned on at the same time in the human body and DNA methylation may be a confounding factor in the gene expression seen in Huntington’s Disease (HD).

Researchers have been studyng how disease may be correlated to errors in methylation.  Specifically in trinucleotide repeat disorders DNA methylation may play a role in the stability of the trinucleotide.  Remember HD is a trinucleotinde repeat disorder and those diagnosed have expansions of the CAG portion of the DNA strand.  DNA methylation may also play a role in somatic and germinal cell stability. 

Germinal mutations are mutations of genes in a germ cell and a somatic mutation is a mutation of genes in all other cells.  Research has shown that the CAG repeat expansion in HD is due to somatic instability and potentially finding a way to alter the instability would lead to therapeutic advantages (Swami, 2009).  This study as well as others show that this somatic instability is also related to the age of onset of the symptoms of the disease.

The most promising treatment coming out of Western medicine seems to be the use of antisense oligonucleotides (ASO).  These are gene silencing drugs that act upon the defect in the Huntington gene.  Basically, they destroy the defective mRNA before it can ever be transcribed into DNA. 

In monkeys they injected the drugs into the spinal fluid and saw a reversal of symptoms as well as a decreased amount of the abnormal Huntington protein.  The only issue now is making sure that the drugs do not block the normal Huntington protein, as it is important for human development (http://www.genengnews.com/gen-news-highlights/antisense-oligos-reverse-huntington-disease-phenotype-in-mice/81246940/).

As this is promising, what if we can attack this issue from the start by increasing DNA methylation?  This can increase our natural gene silencing abilities.  If we can silence the production of the abnormal Huntington protein without affecting the normal Huntington protein we may be able to silence the symptoms of the disease.  If anything it can prolong the onset of symptoms, or work in conjunction with the new drugs to increase their efficacy.  There will be much more to come on this topic to come.

 

 

http://www.societyns.org/runn/2010/pdfs/Portela%20Nat%20Biotech%20review%202010%20epigenetic%20mod.pdf

http://www.nature.com/scitable/topicpage/the-role-of-methylation-in-gene-expression-1070

http://hmg.oxfordjournals.org/content/18/16/3039.full
http://bura.brunel.ac.uk/bitstream/2438/7217/2/Fulltext.pdf

I first began looking for someone with Kevin’s credentials at a very rough moment in my life. I was 23 years old, overweight, on depression and anxiety medicine, exhausted, and being told by every medical professional from registered dietician up through a bariatric surgeon specialist that my issues could all be solved by their own specialty. The registered dietician wanted me to eat better – which I did with no results. The personal trainer wanted me to work out 6 days a week, which I did with no results. The primary care physician wanted me on prescription weight loss medicine with 800 calories, which I did with no result. And the bariatric surgeon wanted to cut out my stomach – which got fully approved by my insurance. To put it plainly, the medical industry had failed me.

I needed someone who could take a birds-eye view and catch what thousands of dollars and years of professionals had not.

From my first interaction with Kevin, he’s offered more scientific insight than anyone had ever given me. The information regarding metabolism, adrenals, and neurochemistry has guided me to surround myself with new medical professionals to supplement Kevin’s guidance (all of which have always backed up Kevin completely. I paid a new primary care physician $600 to tell me what Kevin suspected in 10 minutes).

I now have a clear understanding of what has been happening with my body, and on the right track with Kevin and my medical team to reverse it. He caught I had an autoimmune disease called Hashimotos, which caused a lot of the lethargy and depression, and gave me a supplement plan (which I ran by my Dr who agreed with it) which has allowed me to go completely off of all my anti-depressants and anti-anxiety.

In no uncertain terms, I owe finally discovering my thyroid issues, balancing my neurochemistry and coming off medication, and coming onto a path of health and wellness (without cutting out my stomach) all to Kevin.

-Nathan

In my previous entry I discussed how the survival benefit of increased protein p53 inhibits glucose-6-phosphate dehydrogenase, which inturn decreases intracellular glutathione and leads to an increase in reactive oxygen species (ROS).  You can read it here: https://geneticpotential.wordpress.com/2013/03/04/circadian-melotonin-and-huntingtons-disease/.

To help prevent neurogeneration in those diagnosed with Huntington’s Disease we need to find a means to increase intracellular glutathione to combat the ROS.  This is where N-acetylcysteine supplementation comes into play.  N-acetylcysteine (NAC) is a precursor to glutathione.  It also plays a role in modulating the inflammation, glutamatergic, and neurotropic pathways.  New research outlines NAC’s therapeutic use in disorders such as; bipolar disorder, gambling addiction, drug addiction, compulsive disorders, and schizophrenia (Dean, 2011).

Researchers have shown that NAC may be beneficial to those diagnosed with HD.  In one study rats were induced with the disease.  They were given the Wistar strain which inhibits the mitochondria in the striatum.  This is seen in human’s with the disease.  The rats given the strain showed increase ROS and a decrease in antioxidants.  There was an increase in capase 3 expressions as well as p53 in the rats given the Wistar strain.  This is very similar to the mechanisms seen in the human brain.  Capase 3 is important here because it plays a major role in apoptosis, programmed cell death.  An increase in capase 3 leads to an increase in apoptosis.    This lead to neurodegeneration in the rats by means of cognitive decline and motor impairment.  The rats treated with NAC showed a reversal of the symptoms induced by the disease including mitochondrial dysfunction and neurobehavioral deficits (Sandhir, 2012).

Not only is NAC a precursor to glutathione, it is a stimulator of the cystolic enzymes involved in glutathione regeneration.  NAC also has the ability on its own to reduce ROS and it has been shown to prevent apoptosis in cultured neuronal cells and comes with a lack of human toxicity (Benaclocha, 2001).

The other important part of increasing glutathione levels, as I mentioned in my previous article, is through our circadian melatonin levels.  Depression and sleep disorders are very common in patients with HD.  Serotonin is a key player in both aspects.  Serotonin is referred to as our “feel good” neurotransmitter.  Also, when the sunlight goes down our serotonin should be converted into melatonin. I wrote an article about serotonin here:  http://robbwolf.com/2012/10/05/serotonin-deficiency-food-cravings/.

Mouse models have shown an impairment in serotonergenic pathways as the cause for the depression seen in HD patients (Pang, 2009).  Serotonin binding sites in the basal ganglia were decreased in post-mortem human brains.  The basal ganglia is where the decreased GABA and increased dopamine occurs leading to chorea.  Serotonin may play a role in this area as well.  The interesting piece of this study is this same serotonergenic pathway dysfunction was not seen in patients with Parkinson’s disease (Waeber, 1989).  These studies tell us we have a neurotransmitter imbalance problem in the brain causing some symptoms of HD.  To alleviate a decrease in melatonin and to decrease the risk of depression in HD serotonin tissue levels need to remain constant.  5-htp supplementation may be the answer.

In conclusion, patients with HD suffer from increased oxidative stress.  This is due to a decrease in intracellular glutathione.  To increase the levels of that powerful antioxidant supplementing with NAC and restoring tissue levels of serotonin using 5-htp may have positive outcomes in the treatment of HD.

http://www.ncbi.nlm.nih.gov/m/pubmed/22327485/

http://www.ncbi.nlm.nih.gov/m/pubmed/11339849/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044191/

http://hmg.oxfordjournals.org/content/18/4/753.short

http://www.sciencedirect.com/science/article/pii/0306452289900821