Huntington’s Disease (HD) is associated with a genetic mutation that results in an expanded polyglutamine chain in the huntingtin protein. In HD, huntingtin becomes a misfolded protein, which can cause many problems for the nerve cell. Scientists have not yet found a straightforward way to explain how a single genetic mutation can lead to the complex symptoms of HD. It is thought that misfolded huntingtin damages the nerve cell in many different ways.
One proposed mechanism suggests that misfolded huntingtin damages an organelle in the nerve cell called the mitochondrion. Mitochondria are important because they help the cell produce energy and regulate the number of free radicals in the cell. When the mitochondria are not working correctly, oxidative damage occurs in the cell because there are too many free radicals. This is thought to contribute to nerve cell death in HD. Therapies that reduce the amount of free radicals in the nerve cell might prevent some HD symptoms.
One potential treatment to reduce free radicals involves a molecule called coenzyme-Q10, which is naturally produced throughout the body. It plays a role in the electron transport chain and helps produce ATP, the cell’s major source of energy. (For more information on coenzyme-Q10 and the electron transport chain, click here.) Coenzyme-Q10 also reduces oxidative damage by interacting directly with free radicals, inactivating them so they cannot damage the cell. The level of coenzyme-Q10 in the brains of HD patients is lower than normal, potentially reducing the ability of affected nerve cells to manage free radicals that accumulate. Because the nerve cells can no longer deactivate all of the free radicals, they become damaged. Drug supplements may be useful to raise the level of coenzyme-Q10 in the brain and prevent the damage caused by free radicals.
Initial Findings on Coenzyme-Q10^
This section describes several studies that tested the effects of coenzyme-Q10 treatment in both humans and mice. The studies show that coenzyme-Q10 is at least somewhat effective in delaying the symptoms of HD and increasing survival, and could serve as a potential treatment for HD and other neurodegenerative disorders.
Ferrante, et al. (2002) tested coenzyme-Q10 as a treatment in a mouse model of late stage HD. In this study, they found that coenzyme-Q10 given to transgenic mice increased survival by 14.5%. Human trials did not show that coenzyme-Q10 significantly affects survival, so it was thought that coenzyme-Q10 would not make an effective treatment for HD patients. Later research that studied the effects of coenzyme-Q10 in human patients with neurodegenerative disorders similar to HD, such as Parkinson’s disease and ALS, showed that higher doses of coenzyme-Q10 than those previously used produced more promising results. The patients had a significantly declined rate of nerve cell death and symptom progression. (For more information on other neurodegenerative and related diseases, click here.)
The Huntington Study Group (2001) conducted a clinical trial involving 347 early-stage HD patients at various sites in the United States and Canada. The trial was done to test the efficacy of coenzyme-Q10 and remacemide, an anti-glutamate drug. The participants were monitored between July 1997 and June 1998 and were assigned to four different treatments:
- 25% received remacemide
- 25% received coenzyme-Q10
- 25% received a combination of remacemide and coenzyme-Q10
- 25% received a placebo (no medication at all)
The primary measure of the drug’s effectiveness was change in Total Functional Capacity (TFC) of the people with HD. TFC is a standardized scale used to assess capacity to work, handle finances, perform domestic chores and self-care tasks, and live independently. The TFC scale ranges from 13 (normal) to 0 (severe disability). The average TFC score of the participants before the study was 10.2. None of the treatments significantly altered the decline in TFC. However, subjects treated with coenzyme-Q10 showed a delayed decline in the TFC compared to subjects who were not treated translating into approximately one more year of independence for people with HD. The supplement was well-tolerated by the study participants and showed no adverse effects on the participant’s other capacities. No changes in the decline in TFC relative to the placebo group were seen in the participants treated with remacemide. However, improvements in chorea were observed. (For more information on remacemide, an anti-glutamate drug, click here.)
The researchers concluded that although there was a trend toward slowing of the progression of HD with coenzyme-Q10 treatment, the effects were not large enough to recommend coenzyme-Q10 as a treatment for early HD. In part, this is because the financial costs of coenzyme-Q10 are considerable. Since coenzyme-Q10 is a nutritional supplement, it is worth remembering that it is not subjected to the same quality and content regulations as pharmaceutical drugs are. Different brands and formulations of coenzyme-Q10 may differ chemically or may contain additives, and there is little information about how these different contents might affect a person with HD. Finally, it should be emphasized that the findings of this study are not applicable to people at risk for HD, or for people at the intermediate or advanced stages of HD.
Nevertheless, the results of the study suggest that therapies that affect the energy supply in cells can affect the course of HD. Additional studies are called for to identify dosage effects and to study effectiveness for people in different stages of HD.
Koroshetz, et al. (1997) treated 18 early-stage HD patients with oral coenzyme-Q10 for 2 to 8 weeks. The patients were recruited from the Massachusetts General Hospital HD Unit and were all able to walk, with half of them still working. Brain lactate level was used as the criteria to measure the effectiveness of the supplement. They hypothesized that treatment with coenzyme-Q10 could increase the efficiency of the respiratory chain, and consequently, lower lactate levels. (For more on lactate, click here.)
The researchers discovered that upon treatment with coenzyme-Q10, the participants experienced significant decreases in brain lactate levels. Lactate levels reversed back to their original levels following withdrawal of therapy, indicating that the findings were indeed due to coenzyme-Q10 treatment. This study supports the theory that coenzyme-Q10 could increase the amount of energy available in cells, perhaps by increasing the efficiency of the respiratory chain.
Smith, et al. (2006) tested higher doses of coenzyme-Q10 with a late stage HD mouse model. This model demonstrated some features of human HD, including progressive loss of motor function. They also compared two commercially-available preparations of coenzyme-Q10, one from a company called Tishcon and one from a company called Chemco. The researchers administered different doses of each substance, seeking an optimal dosage to treat HD.
Results showed that higher doses of coenzyme-Q10 significantly slowed the progression of HD symptoms, such as declining motor performance and grip strength. Smith tested several different doses and found that for the Chemco formulation of coenzyme-Q10, 5000 mg/kg/day was the most effective dosage in extending the lifespan of HD mice. Tishcon coenzyme-Q10 extended survival by a greater amount and at a lower dosage of 1000 mg/kg/day. Moreover, HD mice treated with higher doses of coenzyme-Q10 did not lose as much weight, have as much nerve cell death, or form as many huntingtin aggregates as untreated HD mice. Administering high doses of coenzyme-Q10 to mice in the form of a pellet significantly raised the level of coenzyme-Q10 in their bloodstream and nerve cells. These findings suggest that oral administration of the drug would be effective. Finally, high doses of coenzyme-Q10 also significantly reduced the amount of OH8dG (8-hydroxydeoxyguanosine) in the brain. OH8dG is a molecule that appears in unusually high concentrations in the brains of HD patients, and is associated with oxidative stress in the nerve cell. In summary, this study shows that high doses of coenzyme-Q10 can prevent some motor symptoms, prolong lifespan, and reduce oxidative stress and nerve cell death in HD mice. However, doses that are too high are less effective, possibly because of side effects.
In comparing the effectiveness of two commercially available coenzyme-Q10 preparations, the study found that the supplement produced by Tishcon was 5 times more effective in extending lifespan than that produced by Chemco. More of the coenzyme-Q10 in the Tishcon pellet was absorbed into the bloodstream in comparison to the Chemco pellet. It is important to remember that coenzyme-Q10 is a nutritional supplement and can be bought in many different prepared forms. Nutritional supplements are not regulated by Food & Drug Administration (FDA) guidelines Often there is little standardization and poor quality control for these supplements. Little is known about how each of these prepared forms may affect HD patients differently, and so more comparative studies are needed.
The Cure HD Initiative (CHDI), a nonprofit drug development research organization for HD, has recently begun to work on creating treatments for HD using coenzyme-Q10. On August 2, 2006 CHDI announced a partnership with Edison Pharmaceuticals, Inc. Edison is a small company that specializes in drug development for diseases related to problems with mitochondria, oxidative damage, and energy levels in the cell. This partnership will be an opportunity for Edison to specifically focus on oxidative damage in HD. The partnership hopes to develop a second generation coenzyme-Q10 molecule to be used to treat HD. Scientists at Edison Pharmaceuticals will contribute their expertise in the biology and pharmacology of free radicals and oxidative damage, while members of CHDI Foundation will contribute their expertise in HD and drug development.
In early 2009, the Huntington Study Group received funding from the NIH to test safety and tolerability of coenzyme-Q10 in individuals who have tested positive for HD but do not show any motor signs of HD. The study is called PREQUEL (Study in PRE-manifest Huntington’s disease of coenzyme Q10 (UbiquinonE) Leading to preventive trials). The study was conducted at 10 clinical sites throughout the nation and was the first therapeutic research study in pre-manifest HD. The results of this study were published in late 2017 and can be seen here.
Numerous studies conducted in the past decade show that coenzyme-Q10 may prove to be an effective drug in treating HD since it can enhance ATP production. Studies in the past have shown it to significantly delay HD symptoms and increase survival, especially in mice. However, side effects are still common, with gastrointestinal upset being the most common side effect in both human and animal trials. The PREQUEL clinical trial will study the effectiveness of coenzyme-Q10 in delaying the onset of HD in individuals who do not yet exhibit the symptoms of the disease. Overall, coenzyme-Q10 holds promise as a supplement to treat HD.
For further reading^
- Smith KM, Matson S, Matson WR, Cormier K, Del Signore SJ, Hagerty SW, Stack EC, Ryu H, Ferrante RJ. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington’s disease mice. Biochimica et Biophysica Acta 1762 (2006) 616–626.
This study demonstrates that larger doses of coenzyme-Q10 are more effective in treating HD mice. A fairly technical research article.
- Koroshetz, et al. “Energy Metabolism Defects in Huntington’s Disease and Effects of Coenzyme Q sub 10”. Annals of Neurology. 1997, Feb; 41(2): 160-5.
This study used oral supplements of coenzyme-Q10 to raise energy metabolism in nerve cells and lower lactate levels in human HD patients. A technical research article.
- The Huntington Study Group. “A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease.” Neurology. 2001, Aug 14; 57(3): 397-404.
This experiment indicates that the use of remacemide and CoQ10 was not efficient enough to warrant study as a treatment. A fairly technical research article.
- Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG,Hersch SM, Beal MF. “Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease.” The Journal of Neuroscience, March 1, 2002, 22(5):1592-1599
This article is the first study from the Ferrante group about treating mice with low doses of coenzyme-Q10. A technical article.
-A. Zhang, 6-8-10