Researchers Discover How Prion Protein Damages Brain Cells

Human brain tissue with Creutzfeldt-Jakob disease has a sponge-like appearanceTeresa Hammett, Centers for Disease Control and Prevention.

Scientists have gained a major insight into how the rogue protein responsible for mad cow disease and related neurological illnesses destroys healthy brain tissue.

Transmissible spongiform encephalopathies (TSEs) are rare, fatal diseases that cause the brain to develop lesions so that it looks like a sponge. They include "mad cow" disease in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans.

The brain damage in TSEs is caused by abnormal proteins called prions that clump together and accumulate in brain tissue. Prions are unique among infectious agents because they have no genetic material. Rather, they're misfolded forms of proteins normally found in the body. When protein chains are created, they fold into distinct shapes, much like paper folded into origami. If the chains misfold and take the wrong shape, they can't function properly and are sometimes sent to the wrong part of the cell.

The culprit in prion diseases is a protein called PrP. It's normally found on the surface of many cells in the body, including the brain. If a misfolded version of PrP enters the body, it can bind to normal PrP and "convert" it into the misfolded form. This well-studied conversion process is what causes mad cow disease and several other TSEs.

Dr. Oishee Chakrabarti and Dr. Ramanujan S. Hegde, researchers at NIH's Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), wanted to discover how and why prions cause the cellular damage that they do. In previous work, they and others noticed that many of the abnormal forms of PrP were found in the cytoplasm, the gelatinous interior of the cell, rather than on the surface. The "misplaced" proteins were associated with disease in mice, suggesting that PrP was causing harm in the cytoplasm.

The scientists studied a strain of mice with dark mahogany-colored fur caused by a gene called Mahogunin. Mice with defective Mahogunin genes have late-onset neurodegeneration. Their brains, riddled with tiny holes, are similar to those seen in TSE.

In the June 11, 2009, issue of the journal Cell, the researchers demonstrated in a series of experiments that PrP can bind to Mahogunin in the cytoplasm of cells to form protein clusters. This clustering leads to changes within cells very similar to the damage when cells are deprived of Mahogunin.

The researchers next turned to mice that produced altered forms of PrP known to come in contact with the cytoplasm. One of the strains they tested was a mouse version of a human hereditary prion disorder called Gerstmann-Straussler-Scheinker Syndrome, an extremely rare disease that causes progressive neurological deterioration. The researchers discovered that cells in parts of the mouse brains became depleted of Mahogunin. They also spotted changes in certain brain cells similar to those they'd seen in the lab-grown cells.

The findings suggest that some of the neurologic damage in prion diseases is caused by altered forms of PrP that interfere with Mahogunin in the cytoplasm. "PrP probably interferes with other proteins too," Hegde said. "But our findings strongly suggest that the loss of Mahogunin is an important factor."

This discovery sets the stage for efforts to develop strategies to prevent PrP from entering the cytoplasm or to replace depleted Mahogunin.