Mad cow protein found to have a sane side

It’s a devastating disease, changing behavior, causing uncontrolled movements, blindness, coma, and, finally, death. And we all have the makings of it in our heads.

When it topples cows, it’s known as mad cow disease. The human form is called Creutzfeldt-Jakob disease. In sheep, it’s scrapie. It’s a rare malady caused by a misshapen protein known as prion protein, or PrP. The big mystery is why people, cows, sheep, and other mammals have so much of the protein in their bodies, particularly in the brain.

“It’s intriguing to find that PrP, which, when ‘misfolded,’ subjects people and animals to these ravaging diseases, is so abundant in our brains,” notes Jeffrey Macklis, an associate professor of surgery at Harvard Medical School and Massachusetts General Hospital. “Why is it kept in the system if it has the ability to wreak so much havoc? It must have an important function.”

In proteins, form determines function. The strings of amino acids of which proteins are made can twist in one way and be beneficial to a body, but if they fold in another way they can be disastrous to the same body. When a small amount of PrP misfolds, it influences normal PrPs near it, causing them to assume the same shape, a wrecking ball that breaks the brain from the inside out.

Macklis, along with Harvard postdoctoral fellows Jason Emsley and Hande Ozdinler, teamed up with Susan Lindquist and her student Andrew Steele at the Whitehead Institute for Biomedical Research to try to find out what value the Jekyll and Hyde protein might offer.

They studied mice in which the gene that makes PrP was knocked out, and compared it to another group in which the protein was overproduced. Their investigation revealed that PrP is present where nerve cells form in the developing brain of embryonic mice. They also located PrP in a few spots in the adult brain. In both places, PrP increases the number of precursor cells that develop into brain and other nerve cells. In the knockout mice, this new cell production was delayed. But when additional PrP was available, new cells formed at a much faster rate.

“The more PrP a cell has, the faster it becomes a mature nerve cell,” notes Steele.

The good side of PrP was discovered.