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Misfolding the key to protein's ability to kill brain cells

Ohio State University

Illustration shows how prions could enter the brain: up nerve cells (long vertical bluish axon) or carried in blood cells (bottom left). Once there, the prions force naturally formed proteins to change shape and become prions themselves. These prions (purple) may then accumulate in the cell.
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COLUMBUS, Ohio - Researchers may have discovered the mechanism behind how prions - pieces of protein molecules- can kill nerve cells in the brain and lead to some serious degenerative diseases. The key seems to lie in how one particular protein misfolds within an organelle inside the cell, transforming itself into a new agent and then poisoning the neuron in which it was made.

The finding was reported today in one of two papers published in the journal Science by researchers at Ohio State University and the Whitehead Institute for Biomedical Research at MIT. One report offers the best explanation to date of how these diseases - transmissible spongiform encephalopathies, or TSE - are able to destroy individual nerve cells and ultimately kill patients.

The second paper proposes an answer to a puzzle that has boggled researchers trying to understand how the non-infectious forms of these diseases initially gain a foothold. If proven true, then the new findings may have implications for new therapies against these diseases and even offer warnings concerning specific therapies for other maladies.

TSEs can attack most mammals. In humans, the diseases include Creutzfeld-Jakob Disease, Kuru, Fatal familial Insomnia, and Alpers Syndrome. Diseases in animals include scrapie in sheep, chronic wasting disease in deer and bovine spongiform encephalopathy in cattle. In the late 1990s, an epidemic of BSE, or "mad cow disease," in Great Britain forced the slaughter of 3.7 million cattle and nearly annihilated that country's beef industry.

While researchers knew that prions were the causative agent for these diseases, just how they did their damage was unclear. Prion diseases in humans may be hereditary and linked to a genetic flaw or occur sporadically at the rate of about one case per million people. But the disease can also be contagious and spread like an infection. At least 93 people died after exposure to BSE in England led them to develop the human equivalent of the disease.

Strings of amino acids combine to form proteins inside the cell. They are then compressed and folded into a conformation permitting them to function properly. These prion proteins, or PrP, are folded in the endoplasmic reticulum of the cell, then move from that organelle and make their way to the surface of the cell.

But occasionally, the proteins will fold incorrectly, forming a molecule called PrPsc.

"This particular incorrect conformation has been found in the majority of patients who have TSE diseases," explained Jiyan Ma, an assistant professor of molecular and cellular biochemistry at Ohio State. Ma did this work, along with Susan Lindquist, director of the Whitehead Institute at MIT, during his postdoctoral fellowship at the University of Chicago.

"Researchers believe this bad conformation is responsible for the transmission of these diseases," he said.

Forms of misfolding other that PrPsc can also occur and the researchers believe these conformations are responsible for killing nerve cells in the brain in TSE patients.

When they are produced within the endoplasmic reticulum, these other malformed proteins are jettisoned from that organelle into the fluid cytosol which fills the cell. There, other organelles called proteasomes normally disassemble the PrPsc molecules safely into their components.

But Ma and Lindquist discovered that if the proteasomes can't digest PrP quickly enough, the protein accumulates in the cytosol and can alter the cell's metabolism, killing it in the process. "When this small amount of PrP gets out into the cytosol, that causes the toxicity to the neural cells," Ma said.

An inspection of tissue from patients who have died from TSE diseases show the brains appear sponge-like, riddled with empty spaces where healthy neural cells once thrived.

The researchers also discovered that PrPsc is able to spontaneously form within the cytosol. Once there, it can convert normal PrP into PrPsc, aiding in the destruction of host nerve cells and helping the disease to spread from cell to cell. Earlier research by other scientists has suggested that proteasome activity may decrease as a person grows older, which could facilitate PrP's ability to overwhelm these organelles and kill the cell.

Normally, TSE diseases strike during the later years of life. The average age when the disease strikes "sporadically" in patients is 68 years old. Stress and other factors may also slow proteasome activity.

"This is a nice explanation for the neurotoxicity in TSE diseases," Ma said, "and it also explains how the disease can occur sporadically within a population, as well as how the inherited version of the diseases can develop."

In the infectious form of the diseases, Ma said, the PrPsc may somehow alter the cell's metabolism or affect some signaling pathway within the cell, which may lead to an accumulation of PrP in the cytosol, causing the cell to die.

"We've been able to show that PrPsc can initially form in the cytosol by inhibiting the disassembly of PrP by the proteasomes. Once they form there, they continue to multiply. And once the cell dies, PrPsc will be released into the environment to infect neighbor cells," Ma said.

This "spontaneous" production of PrPsc had not been seen inside the cell before.

The work also suggests that researchers who may use proteasome inhibitors -- drugs to slow the function of proteasomes, such as some in clinical trials for new cancer therapies -- may be increasing the risk of prion diseases among patients who might be exposed.

Then again, Ma said, diseases that are treated with proteasome inhibitors develop rapidly while TSE diseases are usually only a risk later in life, so there may be little or no danger. Still, researchers who use proteasome inhibitors in their research should also be cautious. Much more research into the precise role proteasomes play in the whole animal is needed to accurately assess that risk, Ma said.


Robert Wollmann, a professor of pathology at the University of Chicago, was co-author with Ma and Lindquist on one of the two papers in Science. Support for this research was provided by the National Institutes of Health and the Howard Hughes Medical Instititute.

Contact: Jiyan Ma, (614) 688-0408;

Written by Earle Holland, (614) 292-8384;

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