Fibril shape is the basis of prion strains and cross-species prion infection

New research on prions, the infectious proteins behind “mad cow” disease and Creutzfeld-Jakob disease in humans, suggests that the ability of prions in one species to infect other species depends on the shape of the toxic threadlike fibers produced by the prion. Two studies on the topic appear in the 8 April issue of the journal Cell.

Although research suggests that prions from one species rarely infect other species, some scientists believe the species barrier was breached when a new version of Creutzfeld-Jakob disease appeared in humans after several recent epidemics of bovine spongiform encephalopathy or “mad cow” disease. Since then, barriers to the transmission of prion diseases between species “have emerged as a major public health issue,” according to Eric Jones and Witold Surewicz of Case Western Reserve University.

Prion diseases are caused by misfolded variants of the normal prion protein, which aggregate into fibrous tangles called amyloid fibrils and cause fatal wasting of brain tissue. The abnormally folded protein itself appears to act as an infectious agent, transmitting disease without a DNA or RNA genome such as in a virus. Although disease prions seem to infect normal prions by binding to them and forcing them to take on the abnormal configuration, researchers remain uncertain about the exact molecular details of infection.

Earlier studies identified many “strains” of disease prions across mammalian and yeast species. Researchers thought these strains could be defined by differences in the underlying amino acid sequences of the prions. Under this scenario, disease transmission would be more likely between species with similar prion amino acid sequences.

But a few mysteries stood in the way: Some individuals harbored several different prion strains that caused different disease outcomes, even though all the prions shared the same amino acid sequence. In some cases, a single amino acid change in one species could completely change its ability to infect a previously “off-limits” species, Surewicz and colleagues found.

In a study published last year in the journal Molecular Cell, Surewuicz and colleagues also demonstrated that a “preseeding” process between animals with different prion amino acid sequences could overcome species barriers. For instance, mouse prion fibrils normally infect humans but not hamsters. But when mouse prions were brought into contact with hamster prion amyloid fibrils, a new strain of mouse fibrils emerged with the ability to infect hamsters but not humans. The new mouse strain had the same amino acid sequence as the original mouse strain but completely different infectious capabilities.

With the help of atomic-level microscopic observation of prions in humans, mice, and hamsters, Jones and Surewicz discovered that it is the specific shape of the amyloid fibrils, and not the amino acid sequences, that may allow prions from one species to infect another.

In a second Cell study, Jonathan Weissman and colleagues at the University of California, San Francisco came to the same conclusion in their experiments with yeast. They too discovered that the particular shape of a prion amyloid fibril was the determining factor in whether one species of yeast could infect another yeast species.

Just as in the case with the preseeded mice fibrils, a particular fibril shape in Saccharomyces cerevisiae yeast allowed prion transmission to Candida albicans yeast. The transmission event led to a new strain of Candida prion fibrils that could in turn infect Saccharomyces.

Although fibril shape appears to be the deciding infective factor, amino acid sequence is still important because it defines a set of possible preferred fibril shapes that prions can adopt, Weissman says. Species with similar amino acids sequences share an overlapping set of shapes, which helps explain why species with shared sequences have the ability to infect each other.

Surewicz says the next step in their research will be to examine fibril shape differences at much higher resolution. Their experiments also used a shortened version of the mammalian prion protein, so they hope to test the fibril factor in a full-length protein soon.

Jones and Surewicz also note that the new findings offer “the unsettling possibility” that repeated cross-species transmission events might eventually create prion fibril strains that can bridge the infection gap between previously separate animals like humans and elk and deer, which suffer from a prion disease called chronic wasting disease.

Surewicz stresses, however, prion infection between species is still rare. “Fortunately, transmission by eating is very ineffective. There have been hundreds of thousands of bovine spongiform encephalopathy cases, for example, and lots of people exposed to tainted beef products, but very few cases of variant Creutzfeld-Jakob.” He says there “must be protective mechanisms working there, but we don’t know what they are.”