Scientists have long eyed an enigmatic protein called PrP as the culprit behind deadly prion diseases, including "mad cow" disease. Now they've identified one of its functions in healthy animals: helping certain stem cells in bone marrow divide and survive. It's not clear what the find means for the protein's behavior in the brain, but prion experts say that uncovering any function for PrP is a big step forward.
PrP is found throughout the body, and it's especially abundant in the brain. In rare cases, PrP can misfold and clump together, potentially leading to fatal prion diseases. But scientists have long wondered why, if PrP can be so deadly, it exists at all. They suspected that the protein harbors normal functions but have never identified what those are, although there are hints that the protein may play a role in memory (ScienceNOW, 5 January 2004).
The new discovery is accidental. A group at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, stumbled upon PrP as they searched for ways to keep their stem cells dividing in the lab. Stem cell biologist Harvey Lodish and his postdoc Cheng Cheng Zhang found that PrP was "hugely expressed" on the surface of mouse embryo hematopoietic stem cells, which morph into blood and immune cells.
The reason why, the team concludes in the 30 January online Proceedings of the National Academy of Science, is that PrP is needed for hematopoietic stem cells to flourish long-term. To show that, the pair teamed up with Whitehead prion expert Susan Lindquist and her Ph.D. student Andrew Steele. The group irradiated mice to kill their bone marrow, then performed a series of hematopoietic stem cell transplants. The irradiated mice were infused with a mix of hematopoietic stem cells, of which half expressed PrP and half didn't. After a few months, these mice in turn became donors for a new set of irradiated mice. By the third transplant, roughly 75% of circulating blood cells had PrP, showing that stem cells with PrP survived better than those without. As further evidence, the researchers used a retrovirus to re-insert PrP into hematopoietic stem cells; this restored the cell's ability to divide and survive.
"It's clear beyond a shadow of a doubt that they've established a function" for PrP, says Neil Cashman, a neuroscientist at the University of British Columbia in Vancouver, Canada. He hopes the work will shed light on what PrP does in the brain. Man-Sun Sy, an immunologist at Case Western Reserve University in Cleveland, Ohio, who found PrP on bone marrow cells, points out that it's still not clear what the new find means for human health and disease, because mice that lack PrP have normal blood systems.