Diana Davis ’20 and Madison Helsel ’20

If you grew up in the United States, you are most likely familiar with the song “This Land is Your Land”, one of the most famous American folk songs. Though it has been rerecorded and performed by many famous artists, you may not know the original writer and performer, Woody Guthrie. Woody Guthrie was born in 1912 and was, and still is, one of the most influential figures American folk music. He traveled across the U.S. for much of his life, lived through the Great Depression, the Dust Bowl, and World War II, and settled down in New York in the early 1950s. During this time, his health began to deteriorate, and he was hospitalized many times and was misdiagnosed with things from alcoholism to schizophrenia. In 1954, upon his admission to psychiatric hospital, he finally received the correct diagnosis: Huntington’s Disease (HD). Sadly, Guthrie passed from complications of HD in 1967, but following his death, his ex-wife Marjorie Mazia founded the Huntington’s Disease Society of America, and helped bring Huntington’s Disease and the importance of research on the disease to the public eye. This publicity was well needed, as HD was not well known at the time and commonly misdiagnosed (such as the case of Guthrie’s mother, who was institutionalized when he was 14, but posthumously diagnosed)1. Though today there is a lot more information on the disease, there is still a long way to go to curing this fatal disease. Recent research has been looking towards the field of epigenetics to learn more about HD and possible treatments. But first, it is important to fully understand Huntington’s disease and what causes it.

What is Huntington’s Disease?

Huntingtion’s disease is a rare but lethal neurodegenerative disease that causes decay to the nervous system over time. As seen in the figure below, HD causes the brain cells to die, which can greatly affect the structure of the brain.

Figure 1: The structure of a brain of a person without HD, compared to a brain of a person with HD2.

Huntington’s disease has a wide range of symptoms, encompassing physical, psychological, and cognitive changes. Physical symptoms may include decline in voluntary movements, as well as increases in involuntary movements. Psychologically, HD may manifest as mental illnesses, and/or as changes in personality. Cognitively, HD may lead to a decline in mental processes, with dementia developing in later stages3.

Huntington’s disease is a genetic disorder, caused by a mutation in the Huntingtin (HTT) gene. DNA is a sequence made up of four different nucleotides (A,T,C, and G), the order of which determines what protein the gene makes. The HTT gene in every person has a CAG repeat, which is a stretch of DNA in the gene which is made up of a series of the three nucleotides “CAG” repeated multiple times in a row. Each sequence of “CAG” is one repeat. People who have fewer than 35 CAG repeats will not be affected by HD, people who have 36-39 repeats may be affected, and people who have 40 or more repeats will be affected by HD (see Figure 2). The number of CAG repeats can be correlated to how severely and early the disease presents itself.

Figure 2: The top shows a protein produced by a healthy HTT gene, while the bottom shows protein produced by an expanded HTT gene4.

Though there is still confusion surrounding how these repeats in the gene translate to degeneration of the brain, if the severity of the disease were based entirely on genetics, it would make sense that people with the same genetic makeup should have the same symptoms. However, a study of identical twins by Georgiou et al. (1999), suggested that there may be more than just genetics at play in HD5. The study found that even though the twins had the same number of CAG repeats in their Huntingtin gene, their symptoms differed greatly. While one of the twins suffered greater physical decline, the other suffered greater cognitive decline. This study showed that there must be more to Huntington’s disease than just genetics, and from that they decided to look into the field of epigenetics.

Epigenetics is the study of how the expression of genes can be changed, in ways other than changing the sequence of DNA. One common mechanism of epigenetics is changing whether a gene is on or off. When a gene is on, it is transcribing its DNA sequence and making proteins for the cell, and when it is off it is not. You can think about DNA transcription like a car at a stop light; if the stop light is “green”, the car (or the DNA transcription) is going, but when the light is “red” the car is stopped. One of the ways the stoplight can change is based on how DNA is stored in the cell. It fits into cells by wrapping tightly around proteins called histones. When histones are close together, it is harder for the proteins that read DNA to access it, so the stoplight is red, and transcription does not occur. When histones are further apart the DNA is able to be read, so the light is green and the car, or transcription, can go. But what determines how tightly the DNA is wrapped around the histones? One mechanism is a molecule called an acetyl group, which, when attached to histones, pushes them farther apart from each other, thus loosening the DNA. Therefore, when histones have acetyl groups, the light is green, and DNA can be transcribed.

What are HDACs and HDACis?
So if acetyl groups can affect whether genes are on or off, how can the acetyl groups on histones be altered? Histone deacetylases (HDACs) can remove the acetyl groups from histones, causing the histones to tighten and the stoplight to turn red. On the other hand, the job for a histone deacetylase inhibitor (HDACi) is to inhibit HDAC activity which means acetyl groups stay on the histone, and the stoplight is green (see Figure 3).

Though scientists are unsure of how exactly the CAG repeats of the Huntingtin gene translate to the symptoms of Huntington’s disease, it is known that the disease causes cells in the brain to die off. These cells have genes with a red stoplight, which means transcription is off and they can’t function, so they die. Therefore, many researchers believe that we need something like HDACis to turn the stoplight green and keep the genes going6. From this idea, there have been multiple studies testing the possibility of using HDACis for helping treat Huntington’s.

Figure 3. (a) HDACs remove acetyl groups (Ac) from the histone, which causes the DNA to stay tightly wound. (b) HDAC inhibitors prevent HDACs from removing the acetyl group from the histones, allowing the DNA to become more relaxed, and increase the transcription of the gene7.

Research on HDACi Treatments
In vitro
A common way to begin investigation into biological hypotheses is the use of in vitro studies, which are experiments that take place outside of a living organism; for example, cells in a petri dish or a test tube. A study by Thomas et al. (2008) tested a specific HDACi (HDACi 4b) to see how it would affect brain cells6. The goal of this study was to see if using it on the cells would cause the cells to die. This could happen if the HDACi activates a gene whose job it is to cause cell death. This study showed that HDACi 4b does not target all genes in the cell, only specific ones, which means it could activate some genes without killing the cells, making it potentially a good choice to treat Huntington’s disease6.

In vivo
Once it was observed in in vitro studies that HDACi 4b could inhibit some genes without seriously damaging the neurons, studies moved to using the inhibitor in vivo, meaning experimenting with live animals. Mice were bred so they had an onset of symptoms similar to Huntington’s disease that appeared when they were adults, such as weight loss, poor coordination, and difficulty moving. Once their symptoms began appearing, they were fed HDACi 4b, which was dissolved in their water. Mice received the HDACi for 67 days, and they began to show improvements in many areas, including their coordination, movement, and weight6.

Molecularly, what is occurring to make this inhibitor so helpful for Huntington’s disease? There are two possibilities that scientists believe could cause this. The first one is that HDACi 4b directly impacts the genes that are affected by Huntington’s disease. This theory states that Huntington’s disease works by decreasing the acetylation of histones on certain genes, leading to lower amounts of transcription, which causes the degeneration of cells. HDACi 4b blocks this decrease of acetylation, which means that the genes will work normally6.

HDACi 4b could also be a helpful inhibitor because it potentially affects genes involved in the cell cycle and cell death. Neurodegenerative diseases like Huntington’s result in a large amount of cell death. By preventing the removal of acetyl groups from the histones of these genes, there is a decrease in cell death, and therefore the overall cause of the symptoms of Huntington’s is mitigated6.
These previous studies make it seem that HDACi 4b would be a potentially effective treatment for Huntington’s disease; however, it is not a perfect solution. First of all, HDACi 4b does not actually dissolve in water like the earlier experiment suggested. The most likely explanation as to why it dissolved in the previous study was that the water was contaminated, which caused the HDACi 4b to dissolve. Another limitation of HDACi 4b is that the amount that would be needed to reduce the effects of Huntington’s disease in humans would most likely be too high to administer orally8.

Clinical trials
However, all hope is not lost. Even though limitations of HDACi 4b make it seem like an unsuitable treatment for Huntington’s disease, there are many other HDACis that have the potential to be used in treatment. Though the topic of HDACis being used in neurodegenerative diseases is relatively new, there have been clinical trials using HDACis in other treatments. In a review by Suraweera et. al (2018), they examine multiple clinical trials in which HDACi has been used in combination with other treatments to try and fight cancers9. Though there is still much research to be done, early results seem to show that HDACis are effective in decreasing tumor size in some people when used in conjunction with other treatments. Though this study with HDACis do not seem to be a miracle cure, as they only slightly decrease the tumors and they have to be used with other treatments to show any sort of results, it does show that HDACis can be used as a treatment in humans, and gives hope that they may be used eventually in treatments for Huntington’s Disease9.

In Conclusion:
This research of possible epigenetic therapies for Huntington’s disease is of great importance and has the ability to help hundreds of thousands of people. In the US alone, there are 41,000 people who have symptomatic cases of Huntington’s Disease, and 200,000 who are at-risk of inheriting HD, and despite the number of people affected, there is not yet a cure or treatment available to slow or stop the progression10. We have a lot more knowledge about HD since Woody Guthrie was diagnosed, and though the idea of using epigenetics to help HD and other neurodegenerative disorders is fairly new, there is a lot of promising research happening.


  1. Woody Guthrie Official Website (n.d.). Retrieved April 19, 2020, from https://www.woodyguthrie.org/
  2. “Huntington’s Disease.” Healthdirect, Healthdirect Australia, www.healthdirect.gov.au/huntingtons-disease.
  3. “Huntington’s Disease Society of America.” Huntington’s Disease Society of America Home Comments, hdsa.org/.
  4. Newman, Michael E. “New SRM Helps Improve Diagnosis of Huntington’s Disease.” Medical Xpress – Medical Research Advances and Health News, Medical Xpress, 13 Apr. 2011, medicalxpress.com/news/2011-04-srm-diagnosis-huntington-disease.html.
  5. Georgiou, Nellie, et al. “Differential Clinical and Motor Control Function in a Pair of Monozygotic Twins with Huntington’s Disease.” Movement Disorders, vol. 14, no. 2, 1999, pp. 320–325., doi:10.1002/1531-8257(199903)14:2<320::aid-mds1018>3.0.co;2-z.
  6. Thomas, Elizabeth A., et al. “The HDAC Inhibitor 4b Ameliorates the Disease Phenotype and Transcriptional Abnormalities in Huntington’s Disease Transgenic Mice.” Proceedings of the National Academy of Sciences, vol. 105, no. 40, 2008, pp. 15564–15569., doi:10.1073/pnas.0804249105.
  7. Kazantsev, A., Thompson, L. Therapeutic application of histone deacetylase inhibitors for central nervous system disorders. Nat Rev Drug Discov 7, 854–868 (2008).
  8. Beconi, Maria, et al. “Oral Administration of the Pimelic Diphenylamide HDAC Inhibitor HDACi 4b Is Unsuitable for Chronic Inhibition of HDAC Activity in the CNS In Vivo.” PLoS ONE, vol. 7, no. 9, Apr. 2012, doi:10.1371/journal.pone.0044498.
  9. Suraweera, Amila, et al. “Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi.” Frontiers in Oncology, vol. 8, 2018, doi:10.3389/fonc.2018.00092.
  10. “Huntington Disease – Genetics Home Reference – NIH.” U.S. National Library of Medicine, National Institutes of Health, ghr.nlm.nih.gov/condition/huntington-disease.

Featured Image Source

Healthdirect Australia. (n.d.). Huntington’s disease. healthdirect. Retrieved September 5, 2022, from https://www.healthdirect.gov.au/huntingtons-disease

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