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Harnessing cells' snacking habits to treat Huntington's

An international team of researchers has developed a new approach to treating diseases such as Huntington's, which are caused by the build up of malformed proteins. The new treatment encourages our cells to 'eat' the proteins. The work, which was partly funded by the EU under...

An international team of researchers has developed a new approach to treating diseases such as Huntington's, which are caused by the build up of malformed proteins. The new treatment encourages our cells to 'eat' the proteins. The work, which was partly funded by the EU under the Sixth Framework Programme (FP6), is published online by the journal Nature Chemical Biology. Huntington's disease occurs when clumps of a malformed protein called huntingtin build up the brain cells of patients. Symptoms of the disease include abnormal movements and psychiatric disturbances such as depression and dementia. Although the gene which causes the diseases was discovered over a decade ago, there are still no treatments which slow the progression of the disease. Normally, cells get rid of unwanted or misfolded proteins by a process called autophagy ('self eating'), in which the cells 'eat' the proteins by enveloping them in a membrane and breaking them down with enzymes. Autophagy also plays a role in clearing up the proteins associated with other diseases such as spinocerebellar ataxia type 3 and familial Parkinson's disease. Autophagy can be stimulated in mice and flies by administering a drug called rapamycin, an antibiotic used as an immunosuppressant in transplant patients. '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,' said Professor David Rubinsztein of 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.' However, the problem with rapamycin is that when used in the long term, it has a number of side effects. The challenge for researchers is to find a safer way of inducing autophagy in the long term. To do this, the researchers screened thousands of small molecules to see if they would enhance or suppress the ability of rapamycin to slow the growth of yeast. Yeast was chosen as a study organism because it is single celled and therefore less complex for screening purposes. Three of the molecules which were found to enhance the growth-suppressing effects of rapamycin in yeast were also found to induce autophagy by themselves in mammalian cells. In fruit flies, the molecules boosted the cells' ability to get rid of mutant huntingtin. The researchers believe that these autophagy inducers could be used to treat a range of neurodegenerative and infectious diseases, as well as certain forms of cancer. 'These compounds appear to be promising candidates for drug development,' commented Prof 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 the right places in the right concentrations, and with minimal toxicity. These are some of the issues we need to look at now.'

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