What makes mad cows mad: The story of prions

By: Erica Gorenberg

In the years following the first human case of “Mad Cow Disease” or variant Creutzfeldt-Jakob Disease (vCJD), world governments introduced measures meant to prevent the infection of additional animals and to protect humans from the continued spread of the disease.

Diseases like mad cow, or bovine spongiform encephalopathy (BSE) in cows, had been documented in animals and humans throughout the world long before the 2003 outbreak. In humans, Creutzfeldt-Jakob Disease (CJD) was first described in 1920, and Kuru, “the laughing sickness” was discovered in the Fore tribe of Paupa New Guinea in the 1950s. In sheep, the equivalent disease is known as Scrapie, because as the disease progresses, the sheep scrape themselves against anything they can find, causing severe injuries. Although these diseases had been studied for many years, it wasn’t until the the 1980s that researchers understood that, unlike previously known infectious agents like bacteria or virus, these diseases were caused by an infecting protein, also known as a prion.

            Each of the thousands of proteins made in a cell has a specific sequence of amino acid building blocks that denotes how it should fold in order to function properly. Most cells in the human body make PrP, the protein that can cause CJD and the other prion diseases mentioned above, but in unaffected individuals it is harmless. In contrast to the normal form of PrP, its prion variant, PrPSc, has a conformation that is harmful to the cell and that can take the normally-folded version and convert it into the infectious misfolded version. Basically prions are the bad kids that your parents didn’t want you to hang out with in high school.

As if prion proteins weren’t already causing enough damage, PrPSc clumps together, inhibiting the normal function of the cells. When too much protein aggregation occurs, cells activate a suicide pathway, known as apoptosis, in order to prevent the spread of harmful materials by breaking them down. Under normal circumstances, misfolded proteins are broken down, but prion aggregates are resistant to the cell’s normal protein breakdown system, the proteasome. In prion disease, more and more cells die, leaving brain tissue porous and spongy and contributing to the symptoms of the disease. In humans, CJD and Kuru manifest first with dysfunctions in muscle coordination and progress rapidly to include personality changes, memory impairment, dementia and eventually death.

Prion proteins usually infect their hosts through consumption or contact with contaminated material. Only in rare cases do sporadic genetic mutations in the PrP gene lead to heritable prion disease. It seems BSE spread to cows because the protein in their feed came from scrapie-infected sheep. When humans consumed infected cow meat, the prion proteins of the cows were similar enough to pass along PrP misfolding to their human counterparts, creating vCJD.

The prion hypothesis has been controversial since its proposal, but more and more research stands to support the idea of infectious proteins. Now, researchers are able to purify PrP and study animal models that are helping them to understand how this protein may first spontaneously misfold to cause the diseases. Many questions remain unanswered, and a cure for prion disease has yet to be found, but research in this field continues. To understand prion disease, we must learn if PrP, even in its prion form, may exist to aid the cell in some way and whether diseases like Alzheimer’s or depression may be caused by prion-like proteins.


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