Huntingtin gene. As a result, the disease symptoms are caused by some combination of the mutated huntingtin protein, toxic huntingtin RNA, and the extra glutamines encoded by the CAG repeats. Most studies of HD have focused on the central nervous system and the motor defects are widely considered to be the result of neurodegeneration. The laboratory of Dr. Andrew Voss in the Wright State University Department of Biological Sciences has hypothesized that defects caused by the huntingtin gene in skeletal muscle may cause some of the motor symptoms of HD.
In a recent study published in The Journal of General Physiology , researchers at Wright State University and the California State Polytechnic University in Pomona (Cal Poly Pomona) found that muscle maturation is disrupted in the mouse model of HD. A Commentary published in the same issue of the journal provides a more general description of the research. Members of the Voss lab at Wright State who co-authored this paper include the first author, Daniel Miranda (student in Biomedical Sciences PhD Program) and Dr. Shannon H. Romer. Additionally, Dr. Volker Bahn from the Biological Sciences Department is an author on the paper. The results of the study points to an early and progressive disease of muscle tissue that may develop independent of neurodegeneration, which could lead to therapies targeting skeletal muscle to improve patients' motor function according to Voss. "Our results support the idea that HD is a myopathy as well as a neurodegenerative disease and may provide a new opportunity to improve patient care by targeting skeletal muscle tissue," Voss says. In addition, researchers and clinicians may be able to use the skeletal muscle defects as biomarkers to track the progress of HD, a much easier task than examining patients' brain tissue.
This study extended previous work led by Voss while he was at Cal Poly, in which he and colleagues examined late-stage HD mice. The initial focus of the recent work was to compare HD mice with the healthy, wild-type mice (the control group) throughout the course of the disease. They found a progressive reduction in function of a protein called ClC-1 that carries chloride ions into and out of the cells. The disruption in ClC-1 proteins was linked to the disease-causing CAG repeats via problems in mRNA processing. The team found that the defects in ClC-1 function and mRNA processing began before the motor symptoms appeared. Surprisingly, the mRNA encoding ClC-1 was misprocessed in both HD and control mice when they were young, but, as they grew older, only healthy animals were able to start correctly processing the RNA to produce functional ClC-1. This suggested that skeletal muscle maturation was disrupted in the HD mice. They confirmed this by showing that mouse models of juvenile- and adult-onset HD expressed a form of myosin that is normally only found in embryonic and neonatal mice.
Clinically, the early and progressive defects in muscle ClC-1 mRNA processing could be used as a much needed biomarker to assess disease progression in regular HD patients and those receiving test therapeutics. The needle biopsy required to assess mRNA processing in skeletal muscle would be much easier than the current monitoring procedures that involves the use of MRI and PET scans. Additionally, the work reveals novel therapeutic targets for the motor symptoms.