Potential Treatment Target Found for Huntington's Disease

Gene therapy may protect against rare neurodegenerative disorder.

By modifying a specific part of the Huntington gene in a mouse model, researchers found that it prevented cell death and motor impairment, and protects against behavioral symptoms of the disease.

Huntington’s disease (HD) is a rare neurodegenerative disorder that causes the progressive breakdown of nerve cells in the brain, resulting in the deterioration of a person’s physical and mental abilities, according to the Huntington’s Disease Society of America. Some individuals describe HD as having symptoms of ALS, Parkinson’s disease, and Alzheimer’s disease simultaneously.

At this time there is no cure, and the disease is fatal.

HD has been linked to a mutation in the Huntington gene, which causes a protein of the same name to fold up incorrectly. Since neurons are unable to get rid of the misfolded protein, it builds up in the brain, wreaking havoc in the cells.

In a study published in the Journal of Clinical Investigation, researchers were able to demonstrate how modifying the Huntington protein via phosphorylation can make the protein less toxic, and allow it to be eliminated more easily. When a specific spot on the protein S421 was phosphorylated, researchers found that it protected their mouse model of Huntington’s from developing symptoms of HD.

“I was shocked at the profound effect phosphorylation had on the Huntington’s model mice,” said first study author Ian Kratter, MD, PhD. “They showed few signs of the motor dysfunction, depression, or anxiety that are characteristic of the disease. In most of our tests, they were virtually indistinguishable from health mice.”

Another finding was that the mouse models were protected against neuron death, especially in the striatum. Authors noted that they believe the phosphorylation enables the neurons to get rid of more of the harmful protein so that it doesn’t accumulate and damage the cell.

“Phosphorylation helps control how proteins fold and the systems in cells that clear proteins,” said senior study investigator Steven Finkbeiner, MD, PhD. “This is exciting, because a lot of the work we’ve done points to these protein removal pathways as being important not only for Huntington’s disease, but also for other neurodegenerative disorders. Understanding how phosphorylation links to these pathways could help treat several different brain diseases.”

Currently, researchers are exploring different ways to mimic the effects of phosphorylation using a drug.