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Prion Diseases

These diseases

For these reasons, prion diseases are also called transmissible spongiform encephalopathies or TSEs.


Some examples:
Creutzfeldt-Jakob Disease CJD humans
variant Creutzfeldt-Jakob Disease vCJD humans; acquired from cattle with BSE
Bovine Spongiform Encephalopathy BSE "mad cow disease"
Kuru   infectious; in humans who practiced cannibalism in Papua New Guinea
Gerstmann-Sträussler-Scheinker disease GSS inherited disease of humans
Fatal Familial Insomnia FFI inherited disease of humans
Scrapie   infectious disease of sheep and goats
other animal TSEs   cats, mink, elk, mule deer

Before the victim dies of a TSE, the damage to the brain is reflected in such signs as loss of coordination and — in humans — dementia.

Injections of ground-up brain tissue from an animal or human patient with a prion disease into another animal (of the appropriate species) transmits the disease. This suggests that the disease is caused by an infectious agent such as a virus. But viruses have a genome and — despite intense efforts — no evidence of a virus has ever been found in these brain extracts. In fact, treating the extracts with agents (e.g., ultraviolet light) that destroy DNA does not reduce their infectiousness.

To date, the evidence indicates that the infectious agent in the TSEs is a protein.

Stanley Prusiner who has named them prion proteins (designated PrP) or simply prions.

It turns out that prions are molecules of a normal body protein that have changed their three-dimensional configuration.

PrPC

The normal protein

PrPSc

The abnormal, disease-producing protein

Inherited Prion Diseases

Creutzfeldt-Jakob Disease (CJD)

10–15% of the cases of CJD are inherited; that is, the patient comes from a family in which the disease has appeared before.

The disease is inherited as an autosomal dominant.

The patients have inherited at least one copy of a mutated PRNP gene. Some of the most common mutations are: Extracts of autopsied brain tissue from these patients can transmit the disease to These results lead to the important realization that prion diseases can only be transmitted to animals that already carry a PRNP gene with a sequence that is at least similar to the one that encoded the PrPSc. In fact, knockout mice with no Prnp genes at all cannot be infected by PrPSc.

Gerstmann-Sträussler-Scheinker disease (GSS)

This prion disease is caused by the inheritance of a PRNP gene with a mutations encoding most commonly

Again, the disease is also strongly associated with homozygosity for a polymorphism at position 129 (both residues being methionine).

Brain extracts from patients with GSS can transmit the disease to Transgenic mice expressing the P102L gene develop the disease spontaneously.

Fatal Familial Insomnia (FFI)

People with this rare disorder have inherited Extracts from autopsied brains of FFI victims can transmit the disease to transgenic mice.

Infectious Prion Diseases

Kuru

Kuru was once found among the Fore tribe in Papua New Guinea whose rituals included eating the brain tissue of recently deceased members of the tribe. Since this practice was halted, the disease has disappeared.

Before then, the disease was studied by transmitting it to chimpanzees using injections of autopsied brain tissue from human victims.

Scrapie

This disease of sheep (and goats) was the first TSE to be studied. It seems to be transmitted from animal to animal in feed contaminated with nerve tissue. It can also be transmitted by injection of brain tissue.

Bovine Spongiform Encephalopathy (BSE) or "Mad Cow Disease"

An epidemic of this disease began in Great Britain in 1985 and before it was controlled, some 800,000 cattle were sickened by it. Its origin appears to have been cattle feed that The use of such food was banned in 1988 and after peaking in 1992, the epidemic declined quickly.

Creutzfeldt-Jakob Disease (CJD)

A number of humans have acquired CJD through accidental exposure to material contaminated with CJD prions.

Now that both HGH and human gonadotropins are available through recombinant DNA technology, such disastrous accidents need never recur.

Variant Creutzfeldt-Jakob Disease (vCJD)

This human disorder appeared some years after the epidemic of BSE (Mad Cow Disease) swept through the cattle herds in Great Britain. Even though the cow and human PRNP genes differ at 30 codons, the sequence of their prions suggests that these patients (155 by 2005) acquired the disease from eating contaminated beef.

All the patients are homozygous for the susceptibility polymorphism of methionine at position 129.

The BSE epidemic has waned, and slaughter techniques that allow cattle nervous tissue in beef for human consumption have been banned since 1989. Now we must wait to see whether more cases of vCJD are going to emerge or whether the danger is over.

Miscellaneous Infectious Prion Diseases

A number of TSEs have been found in other animals.

Sporadic Prion Diseases

CJD and FFI occasionally occur in people who have no family history of the disease and no known exposure to infectious prions. The cause of their disease is uncertain. Whatever the answer, all the cases are found in people with a susceptibility polymorphism in their PRNP genes.

Prions in Yeast

Two proteins in yeast (Saccharomyces cerevisiae) are able to form prions; that is, they can exist either The greater ease with which yeast can be studied has

Evidence that prions are a "protein-only" phenomenon

Possible basis of species specificity of prions

So the picture that emerges is that a molecule of PrPSc

Although only a small portion of the prion protein is responsible for its specificity, other parts of the molecule are needed for flipping the molecule from the alpha-helical to the beta conformation. All prion proteins contain tracts of repeated Gln-Asn residues which appear to be essential for the conversion process.

Other Pathogenic Prion-like Proteins

The deposits of PrPScin the brain are called amyloid. Amyloid deposits are also found in other diseases.

Examples: With all of these diseases there is evidence that their amyloid-forming proteins, like PrPSc, can

Most cells, including neurons in the brain, contain proteasomes that are responsible for degrading misfolded or aggregated proteins. In the various brain diseases characterized by a build-up of amyloid deposits, it appears that as the small insoluble amyloid precursors accumulate, they bind to proteasomes but cannot be degraded by them. Furthermore, this binding blocks the ability of the proteasomes to process other proteins that are normal candidates for destruction. Because of the critical role of proteasomes in many cell functions, such as mitosis, it is easy to see why this action leads to death of the cell.

Link to discussion of proteasomes.

Prion-like proteins may not always be harmful.

Evidence:

CPEB ("cytoplasmic polyadenylation element binding protein") is a protein that

Perhaps the accumulation of these aggregates at a stimulated synapse causes a long-term change in its activity (memory).

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19 November 2013