As with many neurodegenerative diseases, the accumulation of misfolded protein in the brain is a hallmark of Huntington’s Disease (HD). In HD, these misfolded proteins are mutant huntingtin protein. While normal huntingtin protein is necessary for healthy cellular functioning, research suggests that the accumulation of mutant huntingtin protein causes a toxic gain of function. Recent studies have begun exploring the relationship between HD and gluten, particularly due to gluten’s ability to affect the amount of tissue transglutaminase in the body, an important enzyme in the formation of protein aggregates that are characteristic of HD (or something). Ultimately, the mechanisms our bodies use to digest gluten and the physiological functions affected by HD may have more in common than researchers initially anticipated.
In Huntington’s Disease, not only is there an excess of mutant huntingtin protein, but it also tends to clump together, or aggregate. When the aggregates are in their intermediate stages, they are thought to be associated with cellular function and disease activity. And though the body has ways to get rid of this unwanted material through a process known as autophagy, this function is typically compromised in people with HD. Due to this interaction between mutant huntingtin aggregates and HD disease activity, it is critical to understand how and why these aggregates form, and any factors that influence their formation.
One important class of enzymes to consider when trying to understand protein aggregates in HD is tissue transglutaminases, which are broadly responsible for creating bonds between specific amino acids. Tissue transglutaminases (TGase) play an important role in both autophagy and apoptosis, or programmed cell death, both of which are key processes in maintaining a healthy cell environment. Additionally, the primary role of TGases is to create very strong bonds between specific amino acids, including glutamine. The expanded polyglutamine encoded by the CAG repeat in individuals with HD may serve as an ideal target for TGase activity, which can create bonds between the polyglutamine to create clumps of protein.
There have been many studies looking at this relationship between TGase and HD. This includes studies using drugs such as cystamine to inhibit the effects of TGase and observe the effects on the progression of HD in those individuals. From their clinical trial that concluded in 2015, Raptor Pharmaceuticals claimed to have obtained results that were “clinically meaningful and suggest that [cystamine] may play an important role in the treatment of Huntington’s disease.” For more information about this study please click here. This study and others suggest that limiting the functional activity of tissue transglutaminase may by an effective way to treat the symptoms of Huntington’s Disease, though more research in the field is needed to confirm this idea. To read more about cystamine and HD, please visit this HOPES article.
However, drugs such as cystamine are not the only way to influence the amounts of TGase acting in one’s body. Research suggests that higher amounts of dietary gluten intake is correlated with higher concentrations of TGase in body tissue, including gut and nervous tissue. This relationship between dietary gluten intake and tissue TGase concentration is indirect, acting through a storage protein in wheat called gliadin. While most other dietary proteins are broken down by human gut proteases, gliadin is not, and it consequently reaches the small intestine still in tact. After binding to a receptor there, gliadin is able to cross the intestinal barrier.
Once on the other side of the intestinal barrier, gliadin is catalyzed by TGase, which resides locally in the body tissue. For those who consume gliadin containing foods (including many gluten products) on a normal basis, their bodies must increase TGase activity in order to keep up with the regular intake of gliadin entering the body. This increased TGase, however, is not specific to acting on gliadin, and could possibly affect the formation of HD protein aggregates.
To date, there have been no studies specifically looking at the effects of dietary gluten/gliadin on the progression or severity of HD symptoms. Further research is necessary before the scientific community will be able to accurately assess the relationship dietary gluten can play in HD. However, Buchara et al. in 2004 examined the concentrations of antigliadin antibodies (AGAs) in people with and without HD. This study found a significantly higher concentration of AGAs in HD individuals than in those without HD. Elevated AGA concentrations — a measure that is also used as a diagnostic tool for Celiac Disease — means that individuals with HD may be more sensitive to dietary gluten. Despite this, the basis of association between AGAs and HD is still unclear, which reaffirms the need for research on dietary gluten as an environmental modifier of HD.
For those looking to limit their gluten intake, there are a few options. In addition to replacing gluten containing foods with other healthy alternatives, there are also established diets, such as the Paleo Diet, which are considered gluten free. Please make sure to consult your physician before making any changes to your diet. For more information about diet and HD, please refer to this HOPES webpage.
Existing research suggests that dietary gluten intake could increase tissue transglutaminase, which may have unintended consequences for individuals with HD. However, more research in this area is necessary to determine gluten’s role in HD with any degree of certainty. This research provides valuable insight for the HD community, because as science continues to search for holistic treatment and prevention options for HD, methods for treating and delaying the onset of symptoms of HD are valuable for improving quality of life.
Barta, Z., Mekkel, G., & Zeher, M. (2004, August 24). Antigliadin antibodies in Huntington’s disease. Retrieved from https://n.neurology.org/content/63/4/762.2 Click here to read a response to the article Antigliadin Antibodies in Huntington’s Disease, including questions about the article from other scientists and the author’s response.
Bushara, K. O., Nance, M., & Gomez, C. M. (2004). Antigliadin antibodies in Huntington’s disease. Neurology,62(1), 132-133. doi:10.1212/wnl.62.1.132. Click here to read about a study examining the concentrations of antigliadin and other antibodies in Huntington’s Disease vs non-HD individuals.
Bushara, K. O. (2005). Neurologic presentation of celiac disease. Gastroenterology, 128(4), S92-S97. Click here to read about the ways in which Celiac’s Disease manifests as a neurological disorder, and the relationship between gluten insensitivity and HD.
Chin, R. L., & Latov, N. (2005). Peripheral neuropathy and celiac disease. Current treatment options in neurology, 7(1), 43-48. Click here to read about the mechanisms of Celiac’s Disease and how these, particularly transglutaminase, are related to HD.
Hadjivassiliou, M., Williamson, C. A., & Woodroofe, N. (2004). The immunology of gluten sensitivity: Beyond the gut. Trends in Immunology,25(11), 578-582. doi:10.1016/j.it.2004.08.011. Click here to read about the relationship between antigliadin antibodies and gluten insensitivity from the lens of neurology.
Mastroberardino, P. G., & Piacentini, M. (2010). Type 2 transglutaminase in Huntington’s disease: a double‐edged sword with clinical potential. Journal of internal medicine, 268(5), 419-431. Click here to read about the role of tissue transglutaminase in Huntington’s Disease and the some of the methods researchers are using to target this as a treatment for HD.
Walker, F. O. (2007). Huntington’s disease. The Lancet, 369(9557), 218-228. Click here to read more about the general pathophysiology of HD, including more on the protein aggregates that are characteristic of the disease.