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disease protein diseases cjd

The term prion (derived from "proteinaceous infectious particle") refers to an infectious agent consisting of a tiny protein that lacks genes, but can proliferate inside the host, causing slowly developing neurodegenerative diseases in animals and humans. Prions are thought to cause several diseases that attack the brain, such as Creutzfeldt-Jakob disease in humans, scrapie in sheep, and bovine spongiform encephalopathy (mad cow disease) in cows.

The normal form of the prion, PrPc, is a cell-membrane protein that may play a role in nerve signaling in the brain. The very existence of prions has been disputed by researchers ever since these agents were first postulated in 1981 by Stanley B. Prusiner, a neurologist at the University of California at San Francisco, and his collaborators. Since then, however, there has been increasing evidence that it is tiny, virus-like particles lacking genetic material that induce normal proteins to change their shape, causing neurodegenerative diseases in animals and humans. This may explain the onset of diseases previously called "slow viral infections," which are not thought to be caused by viruses.

British radiobiologist Ticvah Alper found the first indication that such an infectious agent might cause disease. In the mid-1970s, Alper found that the infectious agent that causes scrapie, a brain disease of sheep and goats, was extremely small and resistant to ultraviolet radiation, which is known to inactivate genetic material. More evidence accumulated for the existence of prions during the 1980s: for example, the isolation of rods thought to be prion proteins (PrP) from the brains of hamsters infected with scrapie and humans with Creutzfeldt-Jakob disease. The term prion disease now refers to any disease in which there is an accumulation of the abnormal form of PrP, known as PrPSc. The abnormal prion protein has a different shape than the normal protein, and is resistant to enzymes that degrade proteins, such as proteases.

Aggregates of prions appear to compose the amyloid plaques ("clumps") and fibrils (tiny fibers) seen in the brains of infected humans and animals. These insoluble aggregates appear to trap other things, such as nucleic acids, the building blocks of genes. When the abnormal protein gets into the brains of animals or humans, it converts normal prion proteins into the abnormal form. The accumulation of abnormal proteins in the brain is marked by the formation of spongy holes.

In 1994, researchers at the Massachusetts Institute of Technology and the Laboratory of Persistent Viral Diseases at the Rocky Mountain Laboratories of the National Institutes of Health in Hamilton, Montana, reported that, in the test tube, the abnormal form of the prion protein found in hamsters can convert the normal form into the protease-resistant version. In 1993, researchers at the University of California at San Francisco discovered that the normal prion's shape consists of many helical turns, while the abnormal prion has a flatter shape.

Prion diseases can arise by direct infection, by inherited genes that produce the abnormal prion protein, or by genetic mutation. PrPc is encoded by a single gene on human chromosome 20 (chromosome 2 in mice). The prion is thought to arise during translation of the PrPc gene into the protein, during which time it is modified to the PrPSc form. The abnormal form of the protein appears to share the same amino acid sequence as the normal protein, but the modification causes differences in their biochemical properties. This permits separation of the two proteins by biochemical analytical methods. The modification is rare, occurring only about once in a million times in the general population. The onset of this disorder occurs in middle age. However, some mutations of the PrP gene can cause onset of prion disease earlier than middle age.

Of particular interest is the similarity between prion disease and Alzheimer disease, a more commonly known form of dementia. Alzheimer disease occurs when a cell membrane protein, called amyloid precursor protein (APP), is modified into a form called beta (A4). This modified form is deposited in plaques, whose presence is common in elderly people. And like the PrP gene, certain mutations in the APP gene cause this series of events to occur earlier in life, during later middle age.

In humans, prion diseases can occur in one of several forms. Creutzfeldt-Jakob disease (CJD) is a fatal brain disease lasting less than two years. The symptoms include dementia, myoclonus (muscle spasms), severe spongiform encephalitis (brain deterioration marked by a spongy appearance of tissue caused by the vacuolization of nerve cell bodies and cell processes in the gray matter), loss of nerves, astrocytosis (an increase in the number of astrocytes—brain cells that repair damage), and the presence of abnormal protein plaques in neurons. Gerstmann-Straussler-Scheinker syndrome (GSS) is similar to CJD but lasts for more than two years.

Kuru is a fatal, CJD-like form of spongiform encephalopathy lasting less than three years. The symptoms include loss of nerves, astrocytosis, dementia, and sometimes spongiform encephalopathy. Kuru has been reported in tribes people from Papua New Guinea, who had practiced cannibalism, and therefore were directly exposed to a deceased person's diseased brain tissue.

Atypical prion disease is a form of dementia diagnosed by biochemical tests and genetic criteria, but does not otherwise resemble CJD closely. Finally, fatal familial insomnia (FFI) is an atypical prion disease characterized by degeneration of the thalamus and hypothalamus, leading to insomnia and dysautonomia (abnormal nervous system functioning).

GSS and atypical prion disease (including FFI) are usually inherited. CJD may be inherited, acquired or sporadic; it is usually neither epidemic nor endemic. However, kuru and CJD that arise as a complication of medical treatment are both acquired by contamination of the patient with PrPSc from another infected human. Human prion disease, however, has never been traced to infection from an animal.

With respect to bovine spongiform encephalopathy (BSE), the issue is one of concern regarding transmission from cattle, or from cattle products, to human beings. While no cases are documented that contain conclusive evidence for cross-species contamination, fear is abound that the possibility exists and is therefore a viable threat to public health and safety.

BSE, or mad cow disease, was first identified in a laboratory in Weybridge, England in 1988. Since then, a great deal of public concern has been raised about BSE and beef products. After the initial realization of the prion nature of the infectious agent, the UK government introduced legislation that required destruction and analysis of all cattle suspected of BSE infection. Likewise, all animals to be slaughtered are to be inspected specifically for BSE according to the new legislation. In 1997, an addendum to the laws surrounding BSE stated that specified risk material containing beef matter was to be banned from animal feed, cosmetic and pharmaceutical preparations, as well as including new rules on beef labeling and tracing procedures. While initiated in 1988, the epidemic reached a peak in 1993 with thousands of cows affected, believed to have been caused by contaminated feed. Fear from other countries, including the United States, stemmed from the belief that tainted British beef products held the possibility of causing CJD in humans. In reality, there is only a limited link between BSE and CJD in humans. Since the 1993 epidemic, however, the British Ministry of Agriculture, Fisheries, and Food (BMAFF) reports a steady and continual decline in the number of cases of mad cow disease.

CJD, GSS, and atypical prion dementia are not different diseases; rather, they are descriptions of how prion infection affects individual patients. In fact, members of the same family can have three distinct versions of a prion infection linked to the same mutation. Indeed, it was the demonstration that inherited cases of human transmissible spongiform encephalopathy were linked to PrP gene mutations that confirmed prions are central to these diseases. The concept of PrP gene mutations has subsequently been used for diagnosis and in genetic counseling.

Many specific mutations leading to prion disease have been reported. One example is six point mutations in codons 102, 117, 178, 198, 200, and 217 (a codon is a trio of nucleotides in a gene that codes for a specific amino acid in the protein represented by that gene). Insertional mutations consisting of extra 2, 5, 6, 7, 8, or 9 octapeptide repeats have also been associated with prion disease. The presence of PrP gene mutations does not in itself support a diagnosis of prion disease, however, since not all such mutations produce their characteristic effects in an individual possessing the mutation. Moreover, the presence of such a mutation does not protect the patient from other, much more common neurological diseases. Therefore, in the presence of a PrP gene mutation the patient may not have prion disease, but may have a different brain disease.

Further complicating the picture of prion diseases is the fact that, while spongiform encephalitis is found regularly and extensively in sporadic CJD, in cases of familial CJD it is found only in association with a mutation in codon 200 of the PrP gene. Spongiform encephalitis is not found to any significant extent in other prion diseases.

A particularly notable aspect of prion diseases associated with mutations at codon 198 or 217, is the common occurrence of large numbers of neurofibrillary tangles and amyloid plaques, without spongiform encephalitis. If conventional histological techniques are used, this picture appears indistinguishable from Alzheimer's disease. However, immunostaining of the plaques with antibodies to PrP establishes the diagnosis of prion disease.

One prion disease, CJD, is easily transmissible to animals, especially primates, by injecting homogenates (finely divided and mixed tissues) of brains (rather than pure prions) from cases of acquired, sporadic, or inherited spongiform encephalitis in humans into the cerebrums of animals. However, the disease, which may take 18 months to two years to develop, results from the transformation of PrPc into PrPSc, rather than from the replication of an agent that actually causes the disease.

Moreover, there is experimental evidence for transmission of CJD to humans. The evidence suggests that patients infected by receiving prion-contaminated therapeutic doses of human growth hormone or gonadotropin might pose a threat of infection to recipients of their donated blood.

Critics of the prion hypothesis point out that there is no proof that prions cause neurodegenerative disease. Some researchers point out that very tiny viruses are more likely the agents of what is called prion disease, and that the prion protein serves as a receptor for the virus. In addition, as of 1994, no one had been able to cause disease by injecting prion proteins themselves, rather than brain homogenates.

In 1994, Prusiner received the prestigious Albert Lasker award for basic medical research for his work with prions.

See also Virus.



Pennisi, E. "Prying into Prions: A Twisted Tale of an Ordinary Protein Causing Extraordinary Neurological Disorders." Science News 146 (September 24, 1994): 202-3.

Prusiner, S.B. "Biology and Genetics of Prion Diseases." Annual Review of Microbiology 48 (1994): 655-86.

Prusiner, S.B. "The Prion Diseases." Scientific American 272 (January 1995): 48-51+.

Shaw, I. "Mad Cows and a Protein Poison." New Scientist 140 (October 9, 1993): 50-1.

Wong B-S., D.R. Brown, and M-S Sy. "A Yin-yang Role for Metals in Prion Disease." Panminerva Med. 43 (2001): 283-7.

Marc Kusinitz

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