Infectious, test tube-produced prions can jump the 'species barrier'

Sep 04, 2008

Researchers have shown that they can create entirely new strains of infectious proteins known as prions in the laboratory by simply mixing infectious prions from one species with the normal prion proteins of another species. The findings are reported in the September 5th issue of the journal Cell.

Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are infectious neurodegenerative diseases affecting the brain of several species of mammals including humans. Creutzfeldt-Jakob disease (CJD) is the most common prion disease in humans, along with scrapie in sheep, bovine spongiform encephalopathy (BSE, aka mad cow) in cattle, and chronic wasting disease (CWD) in deer and other cervids.

Unlike conventional infectious microorganisms, the infectious agent in the case of prion diseases consists exclusively of a misfolded form of the prion protein, earlier studies showed.

The researchers now find that prion strains produced by combining normal hamster proteins with infectious mouse proteins can infect hamsters and vice versa. Although they are both rodents, prions from one of the two species normally don't readily infect the other, a common phenomenon amongst prions known as a species barrier, the researchers explained.

The novel prions they produced not only look different, but they also produce symptoms in the animals that differ from any known strain found in nature, they report.

" We are forcing the system by putting everything together, but this suggests that the variety of possible prions is really very large," said Claudio Soto of the University of Texas Medical Branch. "We shouldn't be surprised if new barriers are crossed and new prions arise. There is the potential for a large variety of new infectious prions—some of which may have dramatic effects."

"The infectous agent is nothing like what we're used to," Soto said. "It's just a protein with a different shape from the normal protein we all have." Those misfolded and misshapen proteins can spread by causing normal protein to change their shape. Those aberrant forms band together, forming fibrils.

Soto's team recently reported the generation of infectious prions by amplification of prion misfolding in the test tube. In those experiments, they used a technology called protein misfolding cyclic amplification (PMCA) that mimics some of the fundamental steps involved in the replication of infectious prions in living animals, but at an accelerated rate. The method involves placing small quantities of infectious prions with large quantities of the normal protein from the same species together, allowing the infectious form to imprint on the normal form and thereby replicate itself.

Now, they show that the same method can generate new strains when infectious prions from one species are mixed with normal prion proteins from another species. The finding provides conclusive evidence that the imprinting of disease-causing prions on normal forms can overcome species barriers, and doesn't require any other infectious agent.

This new insight has profound implications for public health, according to the researchers.

" One of the scariest medical problems of the last decades has been the emergence of a new and fatal human prion disease--variant CJD--originated by cross-species transmission of BSE from cattle," the researchers said. BSE has also spread to other animals, including exotic cats, other primates and domestic cats, after they ate feed derived from diseased cows.

The new method might provide insight into the risk that other prion diseases could spread from one species to another, Soto said. For instance, scientists don't know whether chronic wasting disease, a condition now on the rise amongst deer in some parts of the U.S., can be transmitted to humans or not.

Test tube studies like this one might help answer that question, and-- in the case that the deer prions can make the leap—such studies may inform scientists about what those prions might look like, he said. By studying any new prion strains created in mice with the human prion protein, scientists might also gain insight into the potential symptoms associated with those diseases.

" The data demonstrate that PMCA is a valuable tool for the investigation of the strength of the barrier between diverse species, its molecular determinants, and the expected features of the new infectious material produced," the researchers concluded. "Finally, our findings suggest that the universe of possible prions is not restricted to those currently known but that likely many unique infectious foldings of the prion protein may be produced and that one of the sources for this is cross-species transmission."

Source: Cell Press

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JosefHlasny
not rated yet Sep 04, 2008
According to my opinion mad cow disease (BSE)is not an ifectious disease. See my recent presentation at 29th World Veterinary Congress (http://www.meet-i...03.pdf);
Neurodegenerative Diseases and Schizophrenia
as a Hyper or Hypofunction of the NMDA Receptors. There is the abstract about this article;
Neurodegenerative diseases, including BSE, Alzheimer%u2019s disease etc. are caused by different mechanisms but may share a final common pathway to neuronal injury due to the overstimulation of glutamate receptors, especially of the N-methyl-D -aspartate (NMDA) receptor subtype. It is generally accepted that the influx of Ca2 as a result of excessive activation of the NMDA receptor underlies the toxic actions of glutamate in many systems. Also, ammonia intoxication leads to excessive activation of NMDA receptors in brain. On the other hand, Mg2 competes with Ca2 at voltage- gated calcium channels both intracellularly and on the cell surface membrane. So, Mg2 can protect against NMDA- induced neurodegeneration and Ca2 deficiency can be important about "NMDA hypofunction" in schizophrenia. In addition there can be another example about hypoglutamatergic condition; cannabinoids are known to inhibit Ca2 channels- glutamate release in schizophrenia, and to inhibit progression of certain neurodegenerative diseases.
There are no scientific references to date in which high intake of crude protein (and potassium) high enough to lead to a state of hyperammonemia (and hypomagnesemia) during the incubation period of the BSE. Therefore there is the first idea of this review; to show the hyperammonemia plus hypomagnesemia"simultaneous" action on the ruminant tissues. So the various clinical symptoms can be observed because the nervous system controlling both voluntary and unvoluntary muscles is affected (Mg and Ca disturbances). If the BSE is involved; a longer- chronic action of corresponding biochemical changes in the blood (CSF) is necessary, to rise irreversible neurodegenerative changes.
Recently was found that elevated manganese in blood was associated with "prion infection" in ruminants. These findings about "manganese theory" act in concert with this "BSE ammonia- magnesium theory". So I will perform some interpretations about this connection and some details will be presented to the Congress, and also second idea of this review; to show that cannabis use can be a proof about the link between the NMDA receptor hyperfunction (neurodegeneration) and hypofunction (schizophrenia).
Sincerely,
Josef Hlasny,DVM,PhD., Czech Republic
HenisDov
not rated yet Sep 05, 2008
Neurodegenerative Diseases, Prions, And Life Genesis


A. Involvement of misfolded proteins

http://researchne...ttau.htm

- Alzheimer%u2019s disease is the most common form of dementia among older people. It initially involves the parts of the brain that control thought, memory and language

- In other neurodegenerative diseases, the deposition of aggregates enriched in certain tau isoforms has been reported. When misfolded this otherwise very soluble protein can form extremely insoluble aggregates that contribute to a number of neurodegenerative diseases.


B. Prions, Normal and Pathogenic.

http://blog.360.y...Q--?cq=1]http://blog.360.y...Q--?cq=1[/url]]http://blog.360.y...Q--?cq=1[/url]&p=125
and
http://www.the-sc...page#348

- Infectious prions And misfolded proteins. The infectious isoform of normal PrPC, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation.

- "Scientists are learning more about the protein behind mad cow and Creutzfeldt-Jakob disease, including how to interfere with the proteins' production in the brains of mice. "

- "It%u2019s also a mystery how prions replicate %u2014 they seem to do it without DNA %u2014 and they are difficult to kill."

- But, then, it%u2019s also a mystery how at Genesis RNA-related oligomers replicated without DNA!...


C. Again, a phenomenological relationship...

IMO there is a definite, even if yet vaguely understood, relationship between CJ and Life Genesis phenomena parallel to the phenomenological relationship between black-holes and biosphere phenomena.

Black-holes and Biosphere(s?) are both phenomena of constrained energy pockets within a universe of an expanding energy matrix.

CJ and Life Genesis are both phenomena of serendipitous occurrence of 'favourably-directed' energy potential:

- in the case of life genesis, between incoming sun's radiation and RNA-related oligomeric configuration, and

- in degenerating proteins replication, between specific protein-forming-folding-enzymes and enzymes-protein complexes.


musing,

Dov Henis

http://blog.360.y...Q--?cq=1]http://blog.360.y...Q--?cq=1[/url]]http://blog.360.y...Q--?cq=1[/url]

==========================

Life Manifest

Recapitulation of some earlier notes on
The Drive, Nature And Purpose Of Life: Scientific Comprehension

http://www.physfo...ic=14988&st=195&#entry330517


A. Uniqueness Of science among human artifacts

ALL aspects of our culture are, of course, anthropoartifacts, including science. Yet among those artifacts science has a distinct uniqueness for us.

During the recent several centuries in the course of human history humans have been developing science at an accelerating rate as a provider of convincing, ever closer approaching, approximate models of the real world.


B. The drive and nature of life

The drive of life and of its evolution is to enhance the functionality and survivability of the genes, in order to maintain and enhance Earth-biosphere's temporary constrained energy storage and to maintain it BIO as long as possible.

It is the genes, life's prime strata organisms, that evolve, and the evolution of genomes, the 2nd stratum of life, and of the 3rd life stratum cellular organisms, is an interenhancing consequence of their genes' evolution.


C. The nature of life

Earth Life: 1. a format of temporarily constrained energy, retained in temporary constrained genetic energy packages in forms of genes, genomes and organisms 2. a real virtual affair that pops in and out of existence in its matrix, which is the energy constrained in Earth's biosphere.

Earth organism: a temporary self-replicable constrained-energy genetic system that supports and maintains Earth's biosphere by maintenance of genes.

Gene: a primal Earth's organism. (1st stratum organism)

Genome: a multigenes organism consisting of a cooperative commune of its member genes. (2nd stratum organism)

Cellular organisms: mono- or multi-celled earth organisms. (3rd stratum organism)


D. Update of underlying life sciences conception is thus feasible

- First were independent individual genes, Earth's primal organisms.

- Genes aggregated cooperatively into genomes, multigenes organisms, with genomes' organs.

- Simultaneously or consequently genomes evolved protective and functional membranes, organs.

- Then followed cellular organisms, with a variety of outer-cell membrane shapes and
functionalities.

This conception is a scientific, NOT TECHNOLOGICAL, life-science innovation.

It is tomorrow's comprehension of life and of its evolution.

IT IS FRAUGHT WITH INTRIGUING DARWINIAN EVOLUTION IMPLICATIONS.

IT IS FRAUGHT WITH INTRIGUING TECHNOLOGICAL DEVELOPMENTS POTENTIALS.


E. The purpose of OUR, human, life

The purpose of OUR life and its promotion is ours to formulate and set. It derives solely from our cognition.


Suggesting,

Dov Henis

http://blog.360.y...Q--?cq=1]http://blog.360.y...Q--?cq=1[/url]]http://blog.360.y...Q--?cq=1[/url]