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NIAID Scientists Characterize The Most Infectious Prion Protein Particles

Date:
September 8, 2005
Source:
NIH/National Institute of Allergy and Infectious Diseases
Summary:
A new study of prions--apparently malformed proteins that initiate deadly brain diseases such as Creutzfeldt-Jakob disease in humans--has yielded surprising information about how the size of prions relates to their infectivity. Scientists have found that small prions are much more efficiently infectious than large ones, yet there also is a lower size limit, below which infectivity is lost.
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A new study of prions--apparently malformedproteins that initiate deadly brain diseases such as Creutzfeldt-Jakobdisease in humans--has yielded surprising information about how thesize of prions relates to their infectivity. Scientists have found thatsmall prions are much more efficiently infectious than large ones, yetthere also is a lower size limit, below which infectivity is lost.

"Researchers developing treatments for prion diseases can nowfocus on the most efficient purveyors of infection," notes Anthony S.Fauci, M.D., director of the National Institute of Allergy andInfectious Diseases (NIAID), part of the National Institutes of Health,which funded the research. "The persistence and creativity associatedwith this work is admirable." The study appears in the September 8issue of the journal Nature.

Prions appear to consist primarily of an abnormal form of aprotein molecule called PrP. The new research, led by scientists atNIAID's Rocky Mountain Laboratories (RML) in Hamilton, MT, reveals thatthe most infectious prions are significantly smaller than the largethread-like deposits of PrP molecules readily seen in the diseasedbrains of infected individuals. Yet to be infectious, a prion must bemuch larger than the single malformed PrP molecule that has long beenthought to be the basic unit of infectivity.

Prion diseases--also known as transmissible spongiformencephalopathies (TSEs) because the prions create holes in the brain,giving it a sponge-like appearance--include Creutzfeldt-Jakob diseasein humans, mad cow disease in cattle, scrapie in sheep and chronicwasting disease in deer and elk. Scientists have known that infectiousprions range widely in size, but now, for the first time, the RML teamhas ranked them according to their infective efficiency and theirfindings have placed new limits on the size of the smallest prion.

Many neurodegenerative diseases such as Alzheimer's,Parkinson's and TSE diseases are characterized by abnormal proteindeposits in the brain. But questions abound as to what types and sizesof protein deposits are the prime causes of disease.

Prions appear to be crystal-like clusters of PrP molecules thatcan grab normal, dissolved PrP molecules and convert them to a solid,crystal-like state, says RML senior researcher Byron Caughey, Ph.D."Although large prion particles can do this, and are infectious, youcan infect many more individuals, or cause much more rapid disease in asingle individual, with an equivalent weight of small prion particles,"says Dr. Caughey. "But our findings also suggest that if the PrPcluster is smaller than a certain minimum size, it becomes unstable andloses its infectious properties."

Normal PrP molecules found in many animals do not cause harm.But PrP molecules can become lethal and destroy the brain when theyrefold and gather into precisely ordered clusters. This basicinfectious process is reminiscent of disease processes seen with otherprominent neurological diseases, except that in each disease adifferent protein is involved.

The new RML research is consistent with the recently emergingevidence that, in many of the neurological protein aggregationdiseases, small, misfolded clusters are more damaging than largeclusters. Indeed, some scientists have suggested that the largestabnormal protein deposits may be the brain's attempt to sequester manysmall toxic particles into a relatively inert dumping ground.

Thus, Jay Silveira, Ph.D., who spearheaded the RML study,cautions that treatments designed to break apart large accumulations ofprions in the brain might do more harm than good by releasing the mostinfectious prion particles, resulting in more widespread damage thanthat caused by the original large cluster.

"Large deposits, or plaques, could be an attempt by the brainto detoxify the infectivity, to protect the brain," says Dr. Caughey,who oversaw the project. On a graph illustrating how infectivityrelates to PrP particle size, he notes that "as you increase particlesize steadily from single molecules to particles containing thousandsof molecules, there's a sudden jump in infectivity once you get to theminimum infectious particle size (at least six PrP molecules perparticle). Soon the most infectious particles appear (equivalent inweight to 14 to 28 PrP molecules per particle), followed by largerthread-like particles that are still infectious, but less so, per unitof protein," he explains.

The RML group completed its work using a new particleseparation method that should be of interest in studies of otherprotein aggregation diseases, says Dr. Caughey. The process, calledflow field-flow fractionation, or FlFFF, separates particles by size.

"A key to understanding a disease," says Dr. Caughey, "isknowing what to attack and what to ignore: Do we focus on the largeclumps, as scientists initially thought, or their smaller precursors?"

The RML researchers are now trying to isolate the molecularcomponents of the most infectious prions to analyze what else ispresent. "There could be unknown components in there that help theinfection spread," says Dr. Caughey.

He says other researchers may have avoided this particularproject because of the great potential for failure. "This projectinvolved about three years of arduous work and was risky for apostdoctoral researcher looking to establish a career," explains Dr.Caughey. "The separation device we used is not common in our field ofwork, so we had to adapt it to fit our purposes. But the extra workpaid off--now we're providing a new technological approach to solvingimportant questions about these diseases."

That approach included isolating aggregates of infectiousprions from the brains of scrapie-infected hamsters and dispersing theminto detergents. Dr. Silveira then "fractionated" the prions, orseparated them according to physical size, and inoculated them intohamsters. The RML scientists determined the masses of the prionparticles and ranked their infectivity by tracking the number of daysthat passed until the hamsters showed symptoms of scrapie.

Dispersing and fractionating the prions were the mostchallenging parts of the experiment, says Dr. Caughey. "At a certainpoint, the particles become too small to be infectious and they canaccidentally be destroyed," he says. Dr. Silveira used a variety ofprotein dispersion methods, including detergents, sound waves, freezingand thawing, and chemicals, before sorting by size. "He eventuallyfound a set of conditions that worked well to generate very smallparticles that were still infectious," explains Dr. Caughey.

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NIAID is a component of the National Institutes of Health, an agencyof the U.S. Department of Health and Human Services. NIAID supportsbasic and applied research to prevent, diagnose and treat infectiousdiseases such as HIV/AIDS and other sexually transmitted infections,influenza, tuberculosis, malaria and illness from potential agents ofbioterrorism. NIAID also supports research on transplantation andimmune-related illnesses, including autoimmune disorders, asthma andallergies.

Reference: JR Silveira et al. The most infectious prion protein particles. Nature. DOI: 10.1038/nature03989.

News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.


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Materials provided by NIH/National Institute of Allergy and Infectious Diseases. Note: Content may be edited for style and length.


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NIH/National Institute of Allergy and Infectious Diseases. "NIAID Scientists Characterize The Most Infectious Prion Protein Particles." ScienceDaily. ScienceDaily, 8 September 2005. <www.sciencedaily.com/releases/2005/09/050908083333.htm>.
NIH/National Institute of Allergy and Infectious Diseases. (2005, September 8). NIAID Scientists Characterize The Most Infectious Prion Protein Particles. ScienceDaily. Retrieved March 29, 2024 from www.sciencedaily.com/releases/2005/09/050908083333.htm
NIH/National Institute of Allergy and Infectious Diseases. "NIAID Scientists Characterize The Most Infectious Prion Protein Particles." ScienceDaily. www.sciencedaily.com/releases/2005/09/050908083333.htm (accessed March 29, 2024).

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