Understanding and Combating Oxidative Stress in Huntington’s Disease

Written by: Kevin Cann

            Huntington’s Disease (HD) is a rare, genetic, neurodegenerative disorder.  It is a trinucleotide repeat disorder.  This means that trinucleotides in certain genes exceed the normal amount.  The nucleotides are given letters in the DNA.  The trinucleotide that exceeds in number in HD is referred to as the CAG repeat.  The CAG repeat is also referred to as a polyglutamine tract because it consists of several glutamine units.  The polyglutamine tract changes the structure of the cell and the longer it is the more damage it causes (Martindale, 1998).  A normal individual has between 10-28 CAG repeats.  A patient with HD has between 36-120 CAG repeats.  There is some grey area between 28-35 and 36-39.  The ones found to have CAG repeats between 28-35 typically do not develop symptoms or develop symptoms well later on in life.  In the CAG repeats of 36-39 some develop symptoms and some do not.  It is estimated that about 30,000 people in the United States have been diagnosed with HD.  Even though it is a rare disorder a lot of the information we learn from it can be used to help the masses.  The majority of symptoms seen in patients with HD are associated with the diseases of aging such as cognitive decline and psychological issues.  Chorea is another symptom and this involves involuntary movement.  Chorea can be seen in cases of rheumatic fever, pregnancy, and stroke.

Diagnoses for HD are typically done in two ways.  If the mutated gene is known to be in the family, genetic testing is an option.  This can be a difficult decision for someone to make because they may be getting the news that they have a fatal disease.  There is psychological testing that occurs before the test is given to make sure the patient is stable enough to receive the results of the test.  The other way to be diagnosed is when the symptoms of chorea, cognitive decline, and/or behavioral issues begin.  If the patient does know that HD runs in the family this can be a difficult disease to diagnose based on the symptoms.

If the patient has a positive genetic test there are no healthcare options between then and the onset of symptoms.  Once symptoms begin the treatment protocols are just to aid in those symptoms and they do not treat the mechanisms of the disease.  Western medicine seems to have accepted that there is no way to prevent the Huntington gene from expressing itself.  I disagree with this assessment.  There is a lot of quality research that has been done on this disease and it is my opinion that there are protocols that can be followed that can delay the onset of symptoms.  The research points to oxidative stress, energy metabolism issues, decreased DNA methylation, decreased GABA and increased dopamine in the basal ganglia, decreased serotonin receptor sensitivity, and increased tissue transglutamanase as factors in the development of the disease.  The mechanism I will discuss today is the oxidative stress piece and how we can combat that aspect.

Having HD is not all bad.  In fact during childhood and reproductive ages people with HD have better overall health.  They are kind of like X-Men during those years and once they reproduce the symptoms come on and death follows in roughly 20 years.  The survival benefit of having the Huntington gene is a decreased risk of cancer and an increased rate of reproduction.  The latter may just be a result of better overall health as Starks points out in his research paper.  The fact that the disease does not show symptoms until after the age of reproduction indicates that there may be an evolutionary advantage to having this gene as well (Starks, 2007).

The decreased cancer risk is due to an increase in the tumor suppressant protein p53.  Protein p53 plays a role in glucose biosynthesis and consumption.  It does this by inhibiting the enzyme glucose-6-phosphate deyhrogenase (G6PD) (Yang, 2011).  This is important for two reasons.  The first is G6PD is the rate limiting factor for the pentose phosphate pathway.  This alternative pathway to glycolysis pumps out ribose-5-phosphate (R5P), which is involved with the creation of nucleotides.  Studies have shown that modulating levels of ribose-5-phosphate could serve as a treatment for the diseases of aging and polyglutamine tract neurotoxicity (Wang, 2012).

Inhibition of G6PD can also lead to increased apoptosis, programmed cell death.  This is caused by an increase in reactive oxygen species (ROS) (Wang, 1998).  G6PD has another major role and that is in maintaining glutathione levels.  Glutathione is one of our body’s most powerful antioxidants.  Research has shown that the affected genes have higher levels of ROS as well as reduced and oxidized glutathione.  This disappeared when glutathione ethyl ester was given (Ribeiro, 2012).

So how do we increase intracellular glutathione to decrease the damage caused by ROS?  N-aceytlcysteine (NAC) may be the solution.  NAC is a precursor to glutathione and is currently being researched as a solution to addiction and psychiatric issues.  It also plays a role in the glutamatergic pathway.  One of the codons for glutamic acid is CAG and glutamate is a neurotransmitter that plays a role in memory.  CAG repeat extension and cognitive decline are both symptoms of HD.  NAC is also involved in our inflammation response and neurotropic pathways (Dean, 2011).

Studies have also been done looking at NAC’s effects on HD.  In a study performed on rats given the Wistar strain there was a reversal of mitochondria dysfunction as well as behavioral deficits.  The Wistar strain works by inhibiting the mitochondria in the striatum, an area of the brain that is affected by HD.  It also increases intracellular ROS as well as the p53 protein.  This makes it very similar to the presentation of the disease in humans.  There was also in increase in caspase 3, which is a key player in apoptosis.  An increase in caspase 3 leads to an increase in cell death.  This is a major factor in neurodegeneration (Sandhir, 2012).

Most of these studies have been performed on mice.  However, there was one study that was performed on cultured, human neuronal cells.  NAC showed an ability to prevent cell death and reduce ROS on its own.  There is also no known toxicity for NAC and this study also states that NAC is not only a precursor for glutathione, but has the ability to regenerate the powerful antioxidant (Benaclocha, 2001).

There is one more area I would like to address in the terms of oxidative stress and this is our circadian clock.  A common problem throughout the population is dysregulation of our circadian rhythm.  This is important to HD because it also plays a role in glutathione levels.  Dysfunction of the circadian rhythm has been linked to neurodegeneration.  Also, our circadian clock is in charge of our sleep patterns and sleep disturbances are very common in those diagnosed with HD (Beaver, 2012).

When the sun goes down our serotonin should be converted into melatonin.  Melatonin relaxes us and makes us sleepy.  When serotonin levels are low, we encounter too much lights, or there is a problem converting serotonin to melatonin our sleep can get disrupted and this leads to an increase in oxidative stress.  Melatonin has the ability to protect our central nervous system from oxidation.  It actually clears out oxidants and increases the amount of antioxidants in our blood, one of them being glutathione.  Melatonin is also important because it can cross the blood brain barrier very easily (Reiter, 2006).

Serotonin may be important to the pathology of HD for a couple of reasons.  There has to be enough serotonin to convert to melatonin for one.  Also, mouse studies have shown serotonin pathway dysregulation as the cause of depression in HD patients (Pang, 2009).  Also, in post-mortem humans serotonin receptor sites were decreased in the basal ganglia (Waeber, 1989).  This is intriguing because chorea is caused by a decrease in GABA and increase in dopamine in the same area of the brain.  5-htp supplementation may be a necessary means to keep serotonin levels normal.  Also, eating right and following lifestyle habits are important to consider when we look at converting serotonin into melatonin.  I wrote more about serotonin here: http://robbwolf.com/2012/10/05/serotonin-deficiency-food-cravings/.

In conclusion, to decrease oxidative stress we need to increase intracellular glutathione and ensure our circadian clock is working properly.  Supplementing with NAC and 5-htp can aid in this process as well as adopting proper lifestyle habits.  This is important for patients with HD as well as for the general population.  Many diseases are associated with increased oxidative stress including heart disease and cancer.

 

If anyone would like to donate money to help find a cure for this devastating disease visit https://www.hdsa.org/how-you-can-help/donations.html

 

 

 

 

References

http://www.ncbi.nlm.nih.gov/pubmed/9462744

http://www.sciencedaily.com/releases/2011/03/110302142921.htm

http://www.ncbi.nlm.nih.gov/pubmed/22040003

http://ajpcell.physiology.org/content/276/5/C1121.short

http://www.ncbi.nlm.nih.gov/m/pubmed/22982598/

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

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

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

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0050454

http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.1999.tb08028.x/abstract?deniedAccessCustomisedMessage=&userIsAuthenticated=false

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

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

http://ase.tufts.edu/biology/labs/starks/publications/PDF/35.Eskenazietal2007.pdf

 

Kevin Cann

Kevin is the Director of Strength and Conditioning at Total Performance Sports in Boston, MA. Kevin holds a master’s degree in Kinesiology and a bachelor’s degree in health and wellness with an emphasis in nutrition. He is a certified performance enhancement specialist through NASM. He is currently a student of former Team Russia Powerlifting Coach Boris Sheiko. He works with people of all walks of life from rehab, to weight loss, and to competitive athletes. Check out his site at www.totalperformancesports.com