Chemical Tag May Be Ticket Out of Town for Huntington’s

Researchers have discovered a way to use the body’s trash removal system to fight Huntington’s disease (HD), an incurable brain disorder.

The approach is based on a previously unknown ability of neurons to clean away the noxious proteins that clutter the brains of Huntington’s patients. Although this natural mechanism is not enough to keep the disease at bay, researchers have also shown how to enhance it, demonstrating protection against the disease in mouse and worm cells.

“In these models, neuroprotection was very significant,” said Dimitri Krainc, HMS associate professor of neurology at Massachusetts General Hospital and senior author of the study. Krainc and his team think their discovery may yield future treatments that would help brain cells clear away the mutant protein by performing a chemical makeover known as acetylation.

“This study is very significant,” said Leslie Thompson, a professor at the University of California-Irvine who was not involved in the study. “It’s an exciting new target for drug development.”

The disease was first described in 1872 by George Huntington, but much is still unknown about how it does its damage. In 1993, the faulty gene that causes HD was identified. The gene cranks out a mutant protein, dubbed huntingtin, that accumulates inside neurons. This protein buildup seems to trigger the inexorable destruction of neurons that impairs the patients’ ability to move, talk and swallow until it eventually leads to their death.

“You are born with the bad gene, but you live a normal life for 20, 30, 40 years or more,” said Krainc. “Then you get hit.”

More than 30,000 Americans suffer from HD. As in other neurodegenerative diseases like Alzheimer’s and Parkinson’s, current treatments for HD can quench its symptoms but not block disease progression. One of the biggest problems is that Huntington’s is so complex and affects so many processes inside the brain that researchers do not know where to focus. “It just seems that everything you look at in a neuron that expresses mutant huntingtin has been affected,” said Thompson. “There is so much going on.”

Another key similarity among all neurodegenerative diseases is the protein buildup inside the brain. Whether it is Alzheimer’s, Parkinson’s or Huntington’s, the accumulation of misfolded proteins is a hallmark. Many researchers think this accumulation presents a compelling target, although the concept is still controversial. “Everyone would agree that lowering levels of the mutant protein is the key therapeutic goal,” said Krainc.

Eight years ago, Krainc’s group began to study how mutant huntingtin modifies gene function in different models of HD. They found that the mutant protein interferes with the gene expression machinery inside a neuron’s nucleus. More recently, they discovered that neurons can modify mutant huntingtin by sparking the chemical process of acetylation, the addition of acetyl groups. It was the first time that a disease protein was shown to be acetylated. The question was, Why?

After more than five years of research, Krainc and his colleagues discovered that acetylation helps brain cells get rid of the noxious molecule. The chemical process changes huntingtin so it can be picked up by tiny autophagosomes that clear away the refuse inside cells. “They take away useless and accumulated proteins and even organelles such as mitochondria,” said Krainc. “It’s like a trash removal system.”

In a paper published in the April 3 Cell, Krainc and his team showed that acetylation significantly reduced brain damage in a worm model of HD. They also showed that experimental huntingtin that is resistant to acetylation accumulates and causes more brain damage in mice than the unmodified mutant protein. Although the process is still not fully understood, Krainc said, autophagosomes pick up the huntingtin and help break it down into harmless amino acids. Perhaps more importantly, acetylation seems to work preferentially with the mutant version of huntingtin, making it a good potential tool for removing toxic proteins while preserving normal brain function.

Neurons do not clear enough huntingtin to stop the disease, but Krainc’s group came up with a way to give them an extra oomph. They figured out a way to enhance acetylation by blocking the action of certain enzymes called histone deacetylases (HDACs). These are responsible for reverting the effects of acetylation whenever it is needed, so when the team blocked their action, acetylation was enhanced and mutant huntingtin clearance increased.

HDAC blockers are approved cancer drugs. Krainc said that in the future more specific versions of these drugs could be used to help neurons acetylate and get rid of mutant huntingtin. “You just have to boost an ongoing process,” he explained. The team also wants to determine if other disease proteins can be acetylated and digested away by autophagosomes.

The team would also need to watch out for potential side effects. “Getting a drug that could promote this process is going to be a hurdle,” said Thompson.

Krainc’s team is already searching for a better version of HDAC inhibitors that would enhance the cell’s ability to fight HD. The treatment, he said, might be years away, but he hopes not decades.

Students may contact Dimitri Krainc at krainc@helix.mgh.harvard.edu for more information.

Funding Sources: The National Institute of Neurological Disorders and Stroke

Conflict Disclosure: The authors declare no conflicts of interest; the content of the work is the responsibility solely of the authors.