SEEMINGLY different diseases can sometimes share a common cause. Tumours of all sorts, for example, are clusters of cells run out of control, dividing incessantly. Over the past decade, another unifying medical principle has emerged. It holds that many diseases of the central nervous system—including Alzheimer's, Huntington's and Parkinson's diseases—also share a mechanism. Instead of non-stop proliferation, the theme in this case is rubbish-disposal gone wrong.
The garbage in question is abnormally folded proteins. These are usually collected by dustmen (molecules called “ubiquitins” that pick up proteinaceous litter) before being taken to the cell's waste-processing centre (a structure known to biologists as the “proteasome”). Healthy cells create plenty of junk that keeps the system busy. The hundreds of steps of folding that create a complex protein can take a cell many minutes to complete. And with so many steps, mistakes often occur, or toxins push a perfectly configured protein out of place. Such wrongly wrought proteins need to be binned before they cause substantial damage.
In the current issue of the New England Journal of Medicine, Alfred Goldberg of Harvard Medical School, who helped discover the proteasome 20 years ago, discusses what happens to this waste-disposal system when the brain is infected by a particularly nasty protein called a prion. Prions cause Creutzfeldt-Jakob disease (or “mad cow disease” in cattle) by rearranging the structure of normal proteins in their own image. Recently scientists have started to think that prions might also disrupt the rubbish-disposal system, and that such interference might explain how they destroy nerve cells in the brain. Dr Goldberg proposes that globules of prions plug the waste-processing proteasome. That would cause all cellular garbage disposal to cease. Trash would thus remain in the brain until the accumulating filth killed the nerve cells.
Deadly origami
Sarah Tabrizi of University College London, and her colleagues, have also examined the question of how prions kill nerve cells, transforming the brain into a spongy organ riddled with holes. They used a Petri dish of mouse nerve cells and a fluorescent lamp. The cells they studied had been modified to produce a waste protein that glows green under fluorescent light.
First Dr Tabrizi infected the nerve cells with disease-causing prions. Doing so made them grow more luminous as their waste proteins accumulated. Then she added an antibody that cleared the cells of prions but left the ubiquitins, the proteasome and the waste proteins in place. As expected, this made the nerve cells dim because they had regained the ability to dispose of their fluorescent rubbish.
A similar experiment using living mice gave corresponding results. When the mice were infected with prions, ubiquitins collected in their brains. Those ubiquitins were pinned to proteins destined for destruction but, after prions had entered the brains, the junk somehow survived.
Although these tests show that prions can force the waste disposal system to malfunction, they did not identify which part of the process went wrong. So, to work out whether the dustmen were on strike or whether the rubbish-crunching centre had been closed down, Dr Tabrizi purified some proteasomes and took a closer look. By carefully measuring the rate at which proteasomes laboured, she found a clear correlation: as the clumps of prions in the sample got bigger, the proteasomes slowed down. Thus it is the rubbish dump that ceases to work rather than the dustmen neglecting their duties.
That infectious prions cause rubbish to accumulate in brain cells may not be the only way in which they cause damage. Alex Greenwood of the Technical University of Munich, in Germany, and his colleagues, have another idea. They believe that infectious prions might wake viruses that lie dormant in the DNA of an uninfected cell.
Dr Greenwood also works with cells taken from mice. These cells contain disabled viruses because murine ancestors, just like human ones, accumulated them in their genomes whenever infections entered their sex cells. Those historical viruses have been largely disabled by evolution over many millions of years, but they remain, they are numerous, and their genomes constitute about 10% of the DNA of most mammals.
Like Dr Tabrizi, Dr Greenwood infected several types of mouse nerve cells with prions. Next, he examined those cells to see whether they started making the previously disabled viruses. He found some in which this was happening. When he added an anti-prion drug to the mix, though, the virus production halted. The research is reported in Biochemical and Biophysical Research Communications.
Dr Greenwood's data support the theory that prions stimulate brain cells to make viruses that natural selection long put to bed. He thinks that these viruses might even transport prions between nerve cells, spreading the infection to other parts of the brain. If that idea proves correct, prions would be more than flying pickets that closed municipal dumps. They would be muck-spreaders too.
"