For release: Wednesday, June 17, 2009
In Huntington’s disease (HD), a toxic protein accumulates inside brain cells, leading to symptoms such as uncontrolled movements, impaired thinking and personality changes. Researchers have now identified a chemical tag that attaches to this protein, sends it through a cellular waste handling system and prevents its harmful effects. Efforts are underway to identify drugs that could stimulate tagging of the protein and thus slow the course of HD.
“There is widespread agreement that removing the mutant protein from cells would have therapeutic benefits. Our findings suggest it may be possible to modify the protein and make it more susceptible to degradation,” says Dimitri Krainc, M.D., Ph.D., an associate professor of neurology at Harvard Medical School and an investigator at Massachusetts General Hospital in Boston. Dr. Krainc led the study with support from the National Institute of Neurological Disorders and Stroke (NINDS).
HD is a genetic disease, caused by mutations that affect a protein called Huntingtin (Htt). Those mutations elongate the protein and cause it to build up in tangled clumps that interfere with vital cell functions.
The new study, published in Cell*, shows that the attachment of a chemical tag effectively labels mutant Htt as trash. That tag is known as an acetyl group, and it is dealt out by proteins called acetylases. The tagged Htt protein is delivered to an acid-filled structure called a phagolysosome, which is the cellular equivalent of an incinerator.
In an odd twist, Dr. Krainc and his team made their discovery while investigating how the mutant form of Htt affects acetylase proteins, not the reverse. Acetylases do more than mark proteins for destruction. They also regulate gene activity, for example. Some researchers theorize that mutant Htt is toxic primarily because it interferes with acetylases and, hence, with normal gene activity. On that basis, drugs called histone deacetylase (HDAC) inhibitors – which enhance the effects of acetylases – are being explored as potential therapeutics against HD in clinical trials.
The team’s findings suggest that HDAC inhibitors also could stimulate the clearance of mutant Htt from brain cells.
The researchers observed that mutant Htt, and not the normal version of Htt found in healthy brains, is preferentially tagged by acetylases. When they used genetic techniques to insert mutant Htt into neurons, the neurons died. However, when they simultaneously inserted an acetylase with mutant Htt, the neurons were more likely to survive. When the researchers eliminated a site on the mutant protein where the acetyl tag is normally attached, the protective effect of the acetylase was eliminated, too. The researchers also observed the movement of mutant Htt within cells, and found that it was shuttled into phagolysosomes when it carried an acetyl tag.
Finally, in experiments on a mouse model of HD, the researchers found that treatment with HDAC inhibitors reduced the level of mutant Htt in the brain, but did not affect the level of normal Htt. Since HDAC inhibitors can affect many cell functions, a goal of future studies is to identify specific versions of these inhibitors that enhance clearance of the mutant protein without causing harmful side effects.
-By Daniel Stimson, Ph.D.
*Jeong H et al., “Acetylation Targets Mutant Huntingtin to Autophagosomes for Degradation,” Cell, Vol. 137, pp. 60-72, April 3, 2009.
A phagolysosome (orange) is a structure inside cells that disposes of damaged or harmful proteins. Courtesy of Dimitri Krainc.
Last Modified February 9, 2011