Science Editor

Acetylation and deacetylation, via histone deacetylases and acetyltransferases, respectively, help control gene expression by modifying chromosomal structure, making genes more or less accessible to the cell's transcription machinery.

In the April 3, 2009, issue of Cell, researchers showed that acetylation seems to be a more widely used cellular signaling mechanism - and one that may provide another medical use for HDAC inhibitors, already in clinical trials for cancer. In their experiments, they found that increasing the acetylation of mutant huntingtin tagged the protein for destruction by the autophagic/lysosomal system, and that this increased clearance in turn was able to protect both cultured neurons and the worm C. elegans from huntingtin toxicity.

Like amyloid-beta in Alzheimer's and alpha-synuclein in Parkinson's disease, respectively, Huntington's disease is characterized, and possibly caused, by mutated proteins that misfold and then aggregate - or in simpler terms, clump. In Huntington's disease, the problematic protein is huntingtin, and the problematic mutation is a longer-than-normal string of glutamines. Huntington's disease is the most famous of a class of more than 30 diseases caused by such expansions, the so-called polyglutamine diseases.

There is some discussion whether protein aggregations are the root cause of the problems seen is those neurodegenerative diseases, or the brain's attempt at a protective response. But either way, once such clumps form, they are clearly toxic.

In the case of huntingtin, cellular attempts to get rid of such clumps by one form of cellular trash disposal, the ubiquitin-proteasome system, are generally doomed to failure; the huntingtin aggregates are simply too big. "All the proteasome does is . . . spit out the polyglutamine," Dimitri Krainc told BioWorld Today. Krainc is a practicing neurologist and researcher at Massachusetts General Hospital's Institute for Neurodegeneration and Harvard Medical School, and the Cell paper's senior author.

But where the proteasome fails, the autophagosome - which is built to deal with larger cellular debris - picks up.

"The two systems are communicating," Krainc explained. And the signal to the autophagosome to deal with mutant huntingtin - and perhaps other proteins as well - lies in its acetylation.

Krainc and his group realized that acetylation might play a role in targeting proteins to the autophagosome while studying gene transcription and how it is altered in Huntington's and other so-called polyglutamine diseases, which are caused by proteins that contain strings of the amino acid glutamine. The scientists discovered that two of the transcription factors they were studying interacted with huntingtin via an acetyltransferase domain.

In their current Cell paper, the authors first nailed down the specific acetyltransferase and histone deacetylase that interact with mutant huntingtin. They then showed that huntingtin that could not be acetylated formed larger clumps, and was more toxic, than acetylation-sensitive huntingtin. Acetylation of mutant huntingtin significantly reduced neurodegeneration in genetically engineered worms.

Krainc and his team also found that acetylation increased the removal of mutant huntingtin, but had little effect on the normal version of the protein (whose function is as yet unknown).

"One of the major challenges of research into neurodegenerative disorders like Huntington's, Alzheimer's and Parkinson's diseases - all of which involve accumulation of proteins within the brain - has been how to activate degradation machinery that only removes the disease-causing proteins and leaves normal proteins untouched," Krainc said. The new results suggested that for Huntington's disease, increasing huntingtin's acetylation could be such an approach.

HDAC inhibitors are in clinical trials for cancer. But while Krainc said his team was both interested in working with industry to test whether HDAC inhibitors could be useful to treat patients with Huntington's or other polyglutamine diseases, and optimistic about their prospects - "There's so many things that HDAC inhibitors can do" - he also thinks that ultimately, "the secret to success will be to find more specific ones."

Krainc also pointed out that the goals are different when treating cancer patients as opposed to those with neurodegenerative disease. "In cancer, you want to kill the cell. In neurodegeneration, you want to save it. So it is going to be an interesting comparison in terms of the pathways."

Beyond any therapeutic targeting, Krainc and his group also are working on gauging the general importance of acetylation to cellular housekeeping. "We're trying to see whether acetylation of other proteins can also target them for degradation," Krainc said. He believes that acetylation might rise to the level of ubiquitination, or even phosphorylation once researchers start looking at it more closely. "It is the new kid on the block," he said. "It is just gaining momentum now."