A New Twist on Prion Disease

In mad cow disease, misfolded proteins called prions punch holes in the brain, eventually destroying it. Inherited prion diseases, which are rare and passed through families, do the same thing. But it's long been a puzzle why prions attack neurons more than other types of cells, and how they do their damage. In a new study, researchers propose that prions deplete a poorly understood protein that normally keeps nerve cells healthy. The theory still has a ways to go before it's proven, but researchers are intrigued by this potential new twist on a mysterious disease.

Prions are a faulty version of a healthy protein called PrP; when it misfolds, the results are disastrous. Yet researchers don't know exactly why. One argument suggests that whereas healthy PrP is normally located on the cell's surface, prions go astray and end up in the cytosol, the liquid found inside cells, somehow destroying them.

The new study bolsters this theory. The first clues came in a paper published in 2003. In that work, researchers reported that mice lacking an obscure protein, Mahogunin, suffered a form of neurodegeneration much like prion disease. Cell biologists Ramanujan Hegde and Oishee Chakrabarti of the National Institute of Child Health and Human Development in Bethesda, Maryland, decided to probe deeper into the Mahogunin connection.

The team tested whether artificial prion proteins, constructed to resemble real prions, interact with Mahogunin. They did--but because prions are sticky and adhere to almost anything, that wasn't enough proof. So the researchers showed that this interaction caused problems for Mahogunin in living cells: Adding the artificial prion depleted levels of Mahogunin, but when prions were stopped from entering the cytosol, Mahogunin levels remained normal. Finally, mice with a mutation in the PrP gene, which develop prion disease, also lost Mahogunin in some parts of their brains, the duo reports today in Cell.

Although there's no evidence yet that Mahogunin plays a role in infectious prion diseases like mad cow disease, the theory is reasonable for inherited cases, which more closely resemble what's seen in the mice used here, says Adriano Aguzzi, a neuropathologist at the University of Zurich in Switzerland. "On first blush, it is plausible," agrees Neil Cashman, a neuroscientist at the University of British Columbia in Vancouver, Canada, who says the theory needs to be tested further. One issue, says Cashman, is whether the Mahogunin mechanism is compatible with other theories that try to explain prion toxicity, such as those that attribute it to faulty cell signaling.

The authors agree that there are a lot of unanswered questions. One is why a deficit of Mahogunin would harm a cell. Hegde is also interested in whether prions deplete cells of other molecules as well.