BioWorld International Correspondent

LONDON - It may one day be possible to treat conditions such as Huntington's disease by giving drugs that speed up cells' ability to rid themselves of the toxic proteins that cause the harmful symptoms.

A joint team of researchers based in Cambridge, UK, and Cambridge, Mass., has discovered several small molecules that can stimulate faster digestion of harmful proteins in cell models by a process called autophagy, suggesting new therapeutic avenues to treat those diseases.

The drug called rapamycin, which already is in clinical use for people who have had kidney transplants, is known to increase autophagy, but it has unwanted side effects when taken for long periods.

David Rubinsztein, professor of molecular neurogenetics and a Wellcome Trust senior research fellow at the University of Cambridge, UK, told BioWorld International: "We previously showed that one can attenuate the toxicity of the Huntington's disease mutant protein in fly models, cell models and mouse models, if we enhanced autophagy with the drug rapamycin. But because of the side effects of rapamycin, we wanted to find safer ways of inducing autophagy. We have now identified new compounds that can induce autophagy in a rapamycin-independent fashion, and this work provides a strategy for identifying novel drugs that induce autophagy."

Rubinsztein, together with his collaborators, led by Stuart Schreiber of the Broad Institute of Harvard and MIT, published a paper reporting their findings in the May 7, 2007, issue of Nature Chemical Biology. Its title is "Small molecules enhance autophagy and reduce toxicity in Huntington's disease models."

Several human diseases are caused by aggregate-prone proteins. As those build up in the cell, they become toxic, causing various symptoms. For example, the neurodegenerative condition Huntington's disease is caused by an accumulation inside cells of a mutant form of the protein huntingtin. Aggregates of other proteins are known to be the cause of several other diseases, such as spinocerebellar ataxia type 3, certain types of dementia and some forms of Parkinson's disease.

Scientists have hypothesized that, if they could find a way of ridding the cells of the toxic proteins, they might be able to treat the diseases concerned. It seems that cells cannot use one of the normal methods of disposing of such unwanted proteins efficiently via the proteasome (the "cellular dustbin"), because the aggregated proteins are too large to enter it.

One alternative strategy is to encourage faster autophagy. During autophagy, the cell creates a double-walled membrane around a portion of the cytosol, where the unwanted material often is found, forming a structure called an autophagosome. The autophagosome then fuses with enzyme-containing organelles called lysosomes, where its contents are degraded.

Rubinsztein and his colleagues set out to find other ways of inducing autophagy. He said, "We collaborated with Stuart Schreiber's group, who carried out a screen of more than 50,000 compounds for those that modified the ability of rapamycin to slow yeast cell growth, identifying three."

Further experiments showed that the three compounds - which they have called SMERs, for small-molecular enhancers of rapamycin - could by themselves enhance removal of proteins known to be cleared from mammalian cells by autophagy. Although the initial screen was carried out in yeast cells treated with rapamycin, additional tests showed that the effects on autophagy in mammalian cells were independent of rapamycin.

More studies confirmed that the SMERs could reduce the aggregation of the protein huntingtin and lower rates of cell death in cells containing fluorescent-labeled mutant huntingtin.

Rubinsztein and his colleagues confirmed that the mechanism by which the SMERs had their effect was via autophagy. When they added the molecules to similar cells containing labeled huntingtin, but which lacked a key gene required to perform autophagy, there was no effect.

A further experiment involved the use of a Drosophila melanogaster model of Huntington's disease, in which the appearance of the flies' eyes observed by light microscopy makes it possible to monitor the extent of neurodegeneration. When these model flies were treated with each of the three SMERs, they were protected against neurodegeneration, compared with model flies that were treated with a control substance.

"We now need to consider toxicity testing and pharmacokinetic studies," Rubinsztein said. "Eventually, we will carry out trials in rodent models of some of these diseases. We also want to know how the target of rapamycin is linked to the process of autophagy in mammalian cells."