What do mad cow disease and stem cell research have in common? Whitehead Institute scientists have found that the same protein that causes neurodegenerative conditions such as bovine spongiform encephalopathy (mad cow disease) is also important for helping certain adult stem cells maintain themselves.
"For years we've wondered why evolution has preserved this protein, what positive role it could possibly be playing," says Whitehead Member Susan Lindquist. Along with Whitehead Member Harvey Lodish, Lindquist is a coauthor on the paper published online in Proceedings of the National Academy of Sciences. "With these findings, we have our first answer," she says.
For over ten years, researchers have known that a protein called PrP causes mad cow disease and its human equivalent, Creutzfeld-Jakob disease. PrP is a prion, a class of proteins that has the unusual ability to recruit other proteins to change their shape (PrP is shorthand for "prion protein."). This is significant, because a protein's form determines its function. When a prion changes shape, or "misfolds," it creates a cascade where neighboring proteins all assume that particular conformation. In some organisms, such as yeast cells, this process can be harmless, even beneficial. But in mammals, it can lead to the fatal brain lesions that characterize diseases such as Creutzfeld-Jakob.
Curiously, however, PrP can be found throughout healthy human bodies, particularly in the brain where it's highly abundant. In fact, it's found in many mammalian species, and only on the rarest occasions does it result in disease. Clearly, scientists have reasoned, such a widely conserved protein also must play a positive role.
In 1993, scientists created a line of mice in which the gene that codes for PrP was knocked out, preventing the mice from expressing the prion in any tissues. Surprisingly, the mice appeared fine, showing no sign of any ill effect. The only difference between these mice and the control mice was that the knock-out animals were incapable of contracting prion-related neurodegenerative disease when infected. Researchers knew then that PrP was necessary for mad-cow type diseases; any other kind of normal function remained unknown. (There is, however, some weak data suggesting that in certain cultured cells PrP may help prevent cell death.)
Chengcheng Zhang, a postdoctoral researcher in the lab of Harvey Lodish, was studying hematopoietic (blood forming) stem cells in mouse fetal tissue when he discovered that PrP was expressed abundantly on the surfaces of these stem cells. "I found that while not all blood cells with PrP on their surface were stem cells, any cell that lacked PrP was definitely not a stem cell," says Zhang.