Huntington's disease affects muscle as well as brain

New research on mice finds Huntington's disease - a hereditary, progressive disorder involving death of nerve cells in the brain - may also concern defects in skeletal muscle tissue. The finding could lead to better treatments for improving motor function, and it may also offer biomarkers for monitoring the disease without having to examine the brain.

The study - by researchers from Wright State University in Dayton, OH, and California State Polytechnic University in Pomona - is published in The Journal of General Physiology.

People with Huntington's disease increasingly experience uncontrolled movements, poor coordination, muscle rigidity, emotional problems, and loss of cognition or ability to think. The most common form usually appears in a person's 30s or 40s.

The disorder arises from a faulty gene that disrupts the DNA translation and subsequent production of the huntingtin protein, which in turn causes cell malfunction.

Scientists believe the thinking, mood, and behavioral features of Huntington's disease arise from death of nerve cells in the striatum and cerebral cortex regions of the brain.

However, there is speculation that some of the features that affect motor function - such as involuntary movements and muscle rigidity - could be a result of mutant huntingtin in skeletal muscle.

In previous work, the team behind the new study had found mice with an early-onset form of Huntington's disease had defects in their skeletal muscles in the late stages of the disease. They noticed a reduction in function of a protein called ClC-1 that ferries chloride ions into cells.

The defect appeared to be faulty translation of the DNA code for making the ClC-1 protein. This could give rise to hyperexcitability of the muscles and offers a possible explanation for some of the physical movement symptoms of the disease.

Disruption in muscle maturation could be a feature

However, what was not clear from the previous work was whether the defect in protein code processing was just a result of the death of nerve cells controlling the skeletal muscle or whether it arose during onset and progression of the disease.

Fast facts about Huntington's

  • A less common form of Huntington's disease - the juvenile form - begins in childhood or adolescence
  • The disease affects 3-7 per 100,000 people of European ancestry
  • It appears to be less common in other groups, such as people of Japanese, Chinese, and African descent.

Learn more about Huntington's

For their new study, the team looked at what happened in the translation of the DNA code for making the ClC-1 protein during onset and progression of Huntington's disease in mice engineered to develop it. They compared the results with what happens in healthy, wild-type mice (the controls).

The genetic information held in DNA is carried by molecules called messenger RNA to the machinery for making proteins that make cells work. The researchers were interested in what happens to the messenger RNA that carries the code for ClC-1 protein.

They found a defect in the encoding of messenger RNA for ClC-1 protein in both Huntington's and control mice when the animals were young. However, as they aged, the defect corrected itself to produce functional ClC-1 only in the healthy mice.

The finding suggests disruption in muscle maturation could be a feature of Huntington's disease - in mice at least.

On further examination, the team found the Huntington's mice expressed a form of myosin - a motor protein that is normally only found in the muscle of newborn mice. They also found evidence of this in mice with adult-onset Huntington's disease.

"Our results support the idea that HD [Huntington's disease] is a myopathy as well as a neurodegenerative disease and may provide a new opportunity to improve patient care by targeting skeletal muscle tissue."

Senior author Dr. Andrew A. Voss, Wright State University

The researchers also believe the findings offer a way to use biomarkers of skeletal muscle defects to track progress of the disease without having to examine brain tissue in patients.

Learn how Huntington's risk genes are more common than previously thought.

    Progressive Cl− channel defects reveal disrupted skeletal muscle maturation in R6/2 Huntington's mice, Daniel R. Miranda et al., The Journal of General Physiology, doi:10.1085/jgp.201611603, published online 29 November 2016, abstract.

    The Rockefeller University Press news release, accessed 30 November 2016 via Newswise.

    Additional source: Genetics Home Reference, Huntington disease, accessed 30 November 2016.