In Huntington’s disease, abnormally long strands of glutamine in the huntingtin (Htt) protein, called polyglutamines, cause subtle changes in cellular functions that lead to neurodegeneration and death. Studies have shown that the activation of the heat shock response, a cellular reaction to stress, doesn’t work properly in Huntington’s disease. In their research to understand the effects of mutant Htt on the master regulator of the heat shock response, HSF1, researchers have discovered that the targets most affected by stress are not the classic HSF1 targets, but are associated with a range of other important biological functions. Their research is published in the inaugural issue of the Journal of Huntington’s Disease.
In the first genome-wide study of how polyglutamine (polyQ)-expanded Htt alters the activity of HSF1 under conditions of stress, the researchers found that under normal conditions, HSF1 function is very similar in cells carrying either wild-type (natural) or mutant Htt. Upon heat shock, much more dramatic differences emerge in the binding of HSF1. Unexpectedly, the genes no longer regulated by HSF1 were not classical HSF1 targets, such as molecular chaperones and the various genes involved in stress response. The genes that lost binding were associated with a range of other important biological functions, such as GTPase activity, cytoskeletal binding, and focal adhesion. Disorders in many of these functions have been linked to Huntington’s disease in earlier studies; the current research provides a possible mechanism to explain previous observations.
Lead investigator Ernest Fraenkel, PhD, Associate Professor, Biological Engineering, MIT, explains that the impaired ability of HSF1 to respond to stress in these cells is consistent with the slow onset of Huntington’s disease. Although polyQ-expanded Htt is expressed throughout the body, it primarily affects striatum and cortex relatively late in life. “An intriguing hypothesis is that polyQ-expanded Htt sensitizes the cells to various stresses, but is not sufficiently toxic on its own to cause cell death,” he notes. “We have shown that polyQ Htt significantly blunts, but does not completely eliminate, the HSF1 mediated stress response. Over time, the reduced response may lead to significant damage and cell death.”
The findings raise the possibility that activating HSF1 could be an effective strategy for protecting neurons from stress and damage. However, Dr. Fraenkel notes that such a strategy will have to overcome a number of barriers. “HSF1 is highly regulated, and simply increasing its expression may not increase the levels of the active form of HSF1. Also, increased HSF1 levels may raise the risk of cancer, as tumor cells depend on HSF1 activity. Further analysis of the role of HSF1 in neurodegeneration and cancer are critical to uncovering a safe and effective strategy for using HSF1 activation to treat Huntington’s disease.”
In another study published in the inaugural issue of the Journal of Huntington’s Disease, investigators uncover a new biological marker that may be useful in screening antioxidative compounds for the treatment of Huntington’s Disease. Serum 8OHdG is sign of oxidative damage to DNA, and has been shown to be elevated in patients with HD and other neurological disorders. Coenzyme Q (CoQ) is an antioxidant that may slow progression of Huntington’s disease. It is also known to decrease 8OHdG levels in a mouse model of Huntington’s disease. However, it was unknown whether CoQ dosing would reduce 8OHdG in humans.
Investigators administered CoQ to 14 Huntington’s disease patients and 6 healthy controls for 20 weeks. Participants started on 1200 mg/day, and the dosage increased at week 8 to 3600 mg/day. CoQ levels were tested at the beginning of the study and at weeks 4, 8, 12, and 20. Four individuals with Huntington’s disease reported that they were taking CoQ at the start of the study.
Baseline CoQ levels were elevated in individuals with Huntington’s disease compared with health controls, even when individuals who were taking CoQ at the start of the study were excluded, the investigators found. The researchers suggest that individuals with Huntington’s disease may have naturally high levels of CoQ, or some subjects may have recently discontinued CoQ, as CoQ levels can remain elevated in the system for several weeks.
Administration of CoQ led to a reduction of 8OHdG in individuals with Huntington’s disease. While not significant, they found a similar reduction in healthy controls treated with CoQ, suggesting the effect of CoQ on 8OHdG may be non-specific.
“Our study supports the hypothesis that CoQ exerts antioxidant effects in patients with Huntington’s disease and therefore is a treatment that warrants further study,” says lead investigator Kevin M. Biglan, MD, MPH, Associate Professor, University of Rochester. “While the current data can’t address the use of 8OHdG as a surrogate marker for the clinical effectiveness of antioxidants in Huntington’s disease, we’ve established that 8OHdG can serve as a marker of the pharmacological activity of an intervention.”