Prion diseases are disorders of protein conformation

Transmissible spongiform encephalopathies (TSEs) are degenerative brain diseases that occur in many mammals, including humans. In these diseases, the brain gradually develops holes, leaving it looking like a sponge. Scrapie, a TSE that causes affected sheep and goats to rub the wool off their bodies, has been known for 250 years. In the 1980s, a TSE that appeared in cows in Britain was traced to the cows having eaten products from sheep that had scrapie. Then, in the 1990s, some people who had eaten beef from cows with this TSE got a human version of the disease (dubbed "mad cow disease" by the media), again suggesting that the causative agent could cross species lines.

Another instance of humans consuming an infective agent and getting a TSE involved kuru, a disease resulting in dementia that occurred among the Fore tribe of New Guinea. In the 1950s, it was discovered that people with kuru had consumed the brains of people who had died of it. When this ritual cannibalism stopped, so did the epidemic of kuru.

Researchers found that TSEs could be transmitted from one animal to another via brain extracts from a diseased animal. At first, a virus was suspected. But when Tikva Alper at Hammersmith Hospital, London, treated infectious extracts with high doses of ultraviolet light to inactivate nucleic acids, they still caused TSEs. She proposed that the causative agent for TSEs was a protein, not a virus. Later, Stanley Prusiner at the University of California purified the protein responsible and showed it to be free of DNA or RNA. He called it a proteinaceous infective particle, or prion.

Normal brain cells contain a membrane protein called PrPc. A protein with the same amino acid sequence is present in TSE-affected brain tissues, but that protein, called PrPsc, has an altered shape (Figure 17.4). Thus, TSEs are usually not caused by a mutated gene (the primary structures of the two proteins are the same), but are somehow caused by an alteration in protein conformation. The altered three-dimensional structure of the protein has profound effects on its function in the cell. PrPsc is insoluble, and it piles up as fibers in brain tissue, causing cell death.

How can the exposure of a normal cell to material containing PrPsc result in a TSE? The abnormal PrPsc protein seems to induce a conformational change in the normal PrPc

Prpsc Protein

Normal prion protein (PrPc) has many a-helix regions and is relatively soluble.

Abnormal prion protein (PrPsc) has many P-sheet regions and is insoluble.

Normal prion protein (PrPc) has many a-helix regions and is relatively soluble.

Abnormal prion protein (PrPsc) has many P-sheet regions and is insoluble.

17.4 Prion Proteins Normal prion proteins (PrPc, left) can be converted to the disease-causing form (PrPsc, right), which has a different three-dimensional structure.

protein so that it too becomes abnormal, just as one rotten apple results in a whole barrel full of rotten apples. Just how the conversion occurs, and how it causes a TSE, are unclear.

Prions appear to represent a highly unusual phenomenon in human disease. The vast majority of infectious and inherited diseases are understood in terms of proteins that are products of functional or dysfunctional genes. But the expression of these genes, like all genes, is influenced by the environment.

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  • diana
    What diseases result from a disfunctional plasma membrane?
    8 years ago

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