Researchers have found a way of identifying small molecules capable of inducing autophagy without the side effects seen with rapamycin.
Scientists believe that triggering autophagy is a strategy for tackling neurodegenerative diseases such as Huntington's. This disease occurs when the huntingtin protein builds up in the brain cells, mainly in neurons in the basal ganglia and in the cerebral cortex. "We have shown that stimulating autophagy in the cells—in other words, encouraging the cells to eat the malformed huntingtin proteins—can be an effective way of preventing them from building up," says David Rubinsztein, a Wellcome Trust senior clinical fellow at the University of Cambridge. "This appears to stall the onset of Huntington's-like symptoms in fruit fly and mice, and we hope it will do the same in humans."
Mouse and fly models were administered rapamycin, an antibiotic used as an immunosuppressant for transplant patients, to induce autophagy. Over the long term, however, the drug had some side effects, according to the researchers.
The screening process developed by Rubinsztein, Stuart Schreiber’s lab at the Broad Institute of Harvard/MIT, and Cahir O’Kane’s group in the Department of Genetics at the University of Cambridge involves identifying small molecules that enhance or suppress the ability of rapamycin to slow the growth of yeast, though the selected molecules have no effects on yeast growth by themselves.
Of the molecules that enhanced the growth-suppressing effects of rapamycin in yeast, three were also found to induce autophagy by themselves in mammalian cells independent of the action of rapamycin. These molecules enhanced the ability of the cells to dispose of mutant huntingtin in cell and fruit fly models and protect against its toxic effects.
"These compounds appear to be promising candidates for drug development," notes Rubinsztein. "However, even if one of the candidates does prove to be successful, it will be a number of years off becoming available as a treatment. In order for such drugs to be useful candidates in humans, we will need to be able to get them into right places in the right concentrations, and with minimal toxicity. These are some of the issues we need to look at now."
The research is published in Nature Chemical Biology.