Bubble trouble: mad cow proteins may hitch a ride between cells.

The deadly malformed proteins responsible for mad cow disease and similar neurodegenerative illnesses in people and other animals may spread between cells using microscopic bubbles, a new study suggests.

These bubbles, known as exosomes, are spit out of immune cells and a variety of other cell types. Some researchers contend that these mobile balloons enable cells to communicate with each other or exchange material. A few investigators even suggest that HIV, the AIDS virus, exploits exosomes to spread copies of itself among cells (SN: 12/6/03, p. 363).

Prions, the infectious proteins that cause mad cow disease, travel in exosomes, Graca Raposo of the Curie Institute in Paris and her colleagues now conclude. In an upcoming Proceedings of the National Academy of Sciences, they report that prions are secreted from cells in association with proteins and cell membrane material characteristic of exosomes.

Prions are the disease-causing form of a natural brain protein dubbed Pr[P.sub.c], for "prion protein cellular." Fatal illnesses including brain degeneration in cows (mad cow disease), people (Creutzfeldt-Jakob disease), and sheep (scrapie) result when prions convert Pr[P.sub.c] into their own mutant form. Prions can arise from a mutation of the gene for PrP and can be transmitted when animals ingest prion-infected tissue.

Biologists had long attributed these illnesses to viruses, but over the last decade, most scientists have accepted the view that a malformed protein, the prion, can by itself act as an infections agent. The discovery of prions earned Stanley Prusiner of the University of California, San Francisco a 1997 Nobel prize (SN: 10/11/97, p. 226). Even so, the details of how prions spread from cell to cell have not been determined. Some research has indicated that this transmission occurs between cells in direct contact.

"The cell-cell contact idea doesn't really help explain how prions spread through the brain or the rapidity of the spread. It seems as if there must be some other mechanism," says Neil Cashman of University of Toronto. "[Exosomes] could be it." He calls the study by Raposo's group "very intriguing work."

A lecture from a prion researcher about 4 years ago inspired Raposo and her colleagues to explore whether the troublesome proteins had any connection with exosomes. The team worked with rabbit and mouse cells genetically engineered to produce large quantifies of the sheep version of Pr[P.sub.c] protein and its associated prion. In cell secretions, the scientists found vesicles bearing Pr[P.sub.c], prions, and molecular components characteristic of exosomes.

"I think [exosomes are] part of the normal trafficking of the protein," says Raposo.

The investigators also showed that they could produce neurodegeneration by injecting prion-containing exosomes into the brains of rodents. The team is now testing whether similar injections into the bloodstream will also lead to brain damage.

In theory, preventing the release of prion-carrying exosomes could stop, or at least slow, neurodegeneration. For now, says Raposo, there are no drugs that specifically interfere with this process.