Small loop in human prion protein shown to prevent chronic wasting disease.


Chronic wasting disease (CWD), an infectious disease caused by prions, affects North American elk and deer, but has not been observed in humans. Using a mouse model that expresses an altered form of the normal human prion protein, researchers led by the University of California have determined why the human proteins aren’t corrupted when exposed to the elk prions. The opensource study, published in the Journal of Clinical Investigation, identifies a small loop in the human prion protein that confers resistance to chronic wasting disease.

Since the loop has been found to be a key segment in prion protein aggregation, this site could be targeted for the development of new therapeutics designed to block prion conversion state the team.

Prions aren’t microorganisms like bacteria or viruses; they’re simply protein aggregates. Some prion diseases are caused by an inherited genetic mutation, while others are caused by exposure to infectious prions in food. Acquired prion diseases are triggered when a foreign, misfolded prion protein causes the body’s own natural prion proteins to misfold and aggregate.

In addition to chronic wasting disease, examples include scrapie and bovine spongiform encephalopathy, or ‘mad cow disease’, in animals and variant Creutzfeldt-Jakob disease in humans. In humans, prion diseases can cause a variety of rapidly progressive neurological symptoms, such as difficulty walking and speaking, and dementia. These diseases are 100 percent fatal and there is currently no effective treatment.

The researchers theorised that a loop in the human prion protein structure may block the elk prions from binding, as the sequences did not appear to be compatible.

To test this hypothesis the team developed a transgenic mouse that expresses a prion protein that’s identical to the human version, except for a small loop, which they swapped out for the elk prion sequence. When these mice were exposed to the elk prions, they developed chronic wasting disease.

In contrast, control mice expressing the normal human prion sequence resisted infection when exposed to same materials, just as humans seem to, even those who consume venison meat.

This finding suggests that the loop structure is crucial to prion conversion and that sequence compatibility with the host prion protein at this site is required for the transmission of certain prion diseases as well as developing a viable animal model for human prion disease research.

Source:  UC San Diego

 

Atomic space-filling and surface representations of the PrP loop highlight the side chain interactions at the zipper interface.  (A) Atomic space-filling model illustrates the view down the fibril axis. The amino acid side chains of donor cervid PrP (gray) and recipient cervid PrP (white) interdigitate in a class 3 steric zipper. (B) In contrast, the zipper interactions between the donor cervid PrP (gray) and the recipient human PrP (white), which contain yellow side chains (M166, E168, S170, N174), generate a cavity (arrow) between human S170 and cervid N170, as well as steric clash (blue rectangle) between human residue E168 and cervid residue Q168.  Human prion protein sequence elements impede cross-species chronic wasting disease transmission.   Sigurdson et al 2015.

Atomic space-filling and surface representations of the PrP loop highlight the side chain interactions at the zipper interface. (A) Atomic space-filling model illustrates the view down the fibril axis. The amino acid side chains of donor cervid PrP (gray) and recipient cervid PrP (white) interdigitate in a class 3 steric zipper. (B) In contrast, the zipper interactions between the donor cervid PrP (gray) and the recipient human PrP (white), which contain yellow side chains (M166, E168, S170, N174), generate a cavity (arrow) between human S170 and cervid N170, as well as steric clash (blue rectangle) between human residue E168 and cervid residue Q168. Human prion protein sequence elements impede cross-species chronic wasting disease transmission. Sigurdson et al 2015.

 

 

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