Prions

Forensic investigations can often be focused on an illness outbreak or death that is suspected of being of infectious origin. Then, a critical task of forensic scientists is to identify the source of the illness and, if it is determined to be contagious, to track the pattern of the infection in order to help quell the present and future outbreaks.

Bacteria, viruses, fungi, and protozoa are the usual causes of infections. However, within the past several decades, a protein found in the brain has been determined to be the cause of one or more similar diseases of humans and animals (variant Creutzfeld-Jacob disease in humans; Bovine Spongiform Encephalopathy [BSE] or "mad cow" in cattle) that produce a progressive destruction of brain tissue.

The determination of the involvement of the protein, dubbed prion, is an example of forensic science. Post-mortem examinations of tissue samples are geared toward unearthing the indications of prion activity and in detecting the presence of the abnormal form of the protein. As in other infectious disease investigations, establishing the origin of the infection becomes a priority.

Prions are proteins that are infectious. Indeed, the name prion is derived from "proteinaceous infectious particles." The forensically relevant investigations that have implicated prions in degenerative brain diseases have been revolutionary. The discovery of prions and confirmation of their infectious nature overturned a central dogma that infections were caused by intact organisms, particularly microorganisms such as bacteria, 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 degeneration was proposed by Stanley Pruisner. This work earned him the Nobel Prize in medicine or physiology in 1997.

In contrast to infectious agents that are not normal residents 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 surrounds the cells. The protein is also designated PrP (for the aforementioned proteinaceous 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 manufacture 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 disease results when a normally stable PrP is "flipped" into a different 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 2005, the mechanism by which a normally functioning protein is first triggered to become infectious is not known. One hypothesis, known as the virino hypothesis, proposes that the infectious form of a prion is formed when the PrP associates with nucleic acid from some infectious organism. Efforts to find prions associated with nucleic acid have, as of 2005, been unsuccessful.

If the origin of the infectious prion is unclear, the nature of the infectious process following the creation of an infectious 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 unaltered and still-normally functioning prions. The altered proteins 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 ultimately die.

The death of regions of the brain cells produces holes in the tissue. This appearance led to the designation of the disease as spongiform encephalopathy. This appearance is a hallmark of forensic examinations.

The weight of evidence now supports the contention that prion diseases of animals, such as scrapie in sheep and BSE in cattle, 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-Ströussler-Scheinker disease. Other human diseases that are candidates (but as yet not definitively proven) for a prion origin are Alzheimers disease and Parkinsons 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 degeneration. 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 may be ubiquitous features of many organisms and that the protein may have other functions than promoting disease.