Microbiology and Immunology

WORLD OF MICROBIOLOGY AND IMMUNOLOGY Prions

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PPrionsRIONS

Prions are proteins that are infectious. Indeed, the name prion

is derived from “proteinaceous infectious particles.” The dis-

covery of prions and confirmation of their infectious nature

overturned a central dogma that infections were caused by

intact organisms, particularly microorganismssuch as bacte-

ria, fungi, parasites, or viruses. Since prions lack genetic

material, the prevailing attitude was that a protein could not

cause disease.

Prions were discovered and their role in brain degener-

ation was proposed by Stanley Pruisner. This work earned him

the 1997 Nobel Prize in medicine or physiology.

In contrast to infectious agents that are not normal resi-

dents of a host, prion proteins are a normal constituent of brain

tissue in humans and in all mammals studied thus far. The

prion normally is a constituent of the membrane that sur-

rounds the cells. The protein is also designated PrP (for pro-

teinaceous infectious particle). PrP is a small protein, being

only some 250 amino acids in length. The protein is arranged

with regions that have a helical conformation and other

regions that adopt a flatter, zigzag arrangement of the amino

acids. The normal function of the prion is still not clear.

Studies from mutant mice that are deficient in prion manufac-

ture indicate that the protein may help protect the brain tissue

from destruction that occurs with increasing frequency as

someone ages. The normal prions may aid in the survival of

brain cells known as Purkinje cells, which predominate in the

cerebellum, a region of the brain responsible for movement

and coordination.

The so-called prion theory states that PrP is the only

cause of the prion-related diseases, and that these disease

results when a normally stable PrP is “flipped” into a differ-

ent shape that causes disease. Regions that are helical and

zigzag are still present, but their locations in the protein are

altered. This confers a different three-dimensional shape to

the protein.

As of 2002, the mechanism by which normally func-

tioning protein is first triggered to become infectious is not

known. One hypothesis, known as the virino hypothesis, pro-

poses that the infectious form of a prion is formed when the

PrP associates with nucleic acid from some infectious organ-

ism. Efforts to find prions associated with nucleic acid have,

as of 2001, been unsuccessful.

If the origin of the infectious prion is unclear, the nature

of the infectious process following the creation of an infec-

tious form of PrP is becoming clearer. The altered protein is

able to stimulate a similar structural change in surrounding

prions. The change in shape may result from the direct contact

and binding of the altered and infectious prion with the unal-

tered and still-normally functioning prions. The altered pro-

teins also become infective and encourage other proteins to

undergo the conformational change. The cascade produces

proteins that adversely effect neural cells and the cells lose

their ability to function and die.

The death of regions of the brain cells produces holes in

the tissue. This appearance leads to the designation of the dis-

ease as spongiform encephalopathy.

The weight of evidence now supports the contention

that prion diseases of animals, such as scrapie in sheep and

bovine spongiform encephalopathy (BSE—popularly known

as Mad cow disease) can cross the species barrier to humans.

In humans, the progressive loss of brain function is clinically

apparent as Creutzfeld-Jacob disease, kuru, and Gerstmann-

Sträussler-Scheinker disease. Other human disease that are

candidates (but as yet not definitively proven) for a prion ori-

gin are Alzheimer’s disease and Parkinson’s disease.

In the past several years, a phenomenon that bears much

similarity to prion infection has been discovered in yeast. The

prion-like protein is not involved in a neurological degenera-

tion. Rather, the microorganism is able to transfer genetic

information to the daughter cell by means of a shape-changing

protein, rather than by the classical means of genetic transfer.

The protein is able to stimulate the change of shape of other

proteins in the interior of the daughter cell, which produces

proteins having a new function.

The recent finding of a prion-related mechanism in

yeast indicates that prions my be a ubiquitous feature of many

organisms and that the protein may have other functions than

promoting disease.

See also BSE and CJD disease; BSE and CJD disease,

advances in research

Negative stain electron micrograph of prions.

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