Non-infectious Prion Protein Linked to Alzheimer’s Disease
‘Harmless’ prion protein linked to Alzheimer’s disease
Non-infectious prion proteins
found in the brain may contribute to Alzheimer’s disease, researchers have found.
normal prion proteins produced naturally in the brain interact with the amyloid-β peptides that are hallmarks of Alzheimer’s disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-β peptide. It was previously thought that only infectious prion proteins, rather than their normal, non-infectious counterparts, played a role in brain degeneration.
Alzheimer’s disease has long been linked to the build-up of amyloid-β peptides, first into relatively short chains known as oligomers, and then eventually into the long, sticky fibrils that form plaques in the brain. The oligomeric form of the peptide is thought to be toxic, but exactly how it acts in the brain is unknown.
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Prion Proteins, Without Genes, Can Evolve
‘Lifeless’ prion proteins are ‘capable of evolution’
scientists transferred prion populations from brain cells to other cells in culture and observed the prions that adapted to the new cellular environment out-competed their brain-adapted counterparts. When returned to the brain cells, the brain-adapted prions again took over the population.
Charles Weissmann, head of Scripps Florida’s department of infectology who led the study, said: “On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses.
“This means that this pattern of Darwinian evolution appears to be universally active. “In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance.
“Now, this adaptability has moved one level down- to prions and protein folding – and it’s clear that you do not need nucleic acid (DNA or RNA) for the process of evolution.”
He said: “The prion protein is not a clone, it is a quasi-species that can create different protein strains even in the same animal. “The abnormal prion proteins multiply by converting normal prion proteins.
“The implication of Charles Weissmann’s work is that it would be better to cut off that supply of normal prion proteins rather than risk the abnormal prion adapting to a drug and evolving into a new more virulent form.
Related: Challenging the Science Status Quo – Clues to Prion Infectivity – Soil Mineral Degrades the Nearly Indestructible Prion – Bdelloid Rotifers Abandoned Sex 100 Million Years Ago
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Soil Mineral Degrades the Nearly Indestructible Prion
Warped pathogens that lack both DNA and RNA, prions are believed to cause such fatal brain ailments as chronic wasting disease (CWD) in deer and moose, mad cow disease in cattle, scrapie in sheep and Creutzfeldt-Jakob disease in humans. In addition to being perhaps the weirdest infectious agent know to science, the prion is also the most durable. It resists almost every method of destruction from fire and ionizing radiation to chemical disinfectants and autoclaving, which reduce prion infectivity but fail to completely eliminate it.
Other studies have shown that prions can survive in the soil for at least three years, and that soil is a plausible route of transmission for some animals, says Joel Pedersen, a UW-Madison environmental chemist. “We know that environmental contamination occurs in deer and sheep at least,” he notes.
Prion reservoirs in the soil, Pedersen explains, are likely critical links in the chain of infection because the agent does not appear to depend on vectors — intermediate organisms like mosquitoes or ticks — to spread from animal to animal.
That the birnessite family of minerals possessed the capacity to degrade prions was a surprise, Pedersen says. Manganese oxides like birnessite are commonly used in such things as batteries and are among the most potent oxidants occurring naturally in soils, capable of chemically transforming a substance by adding oxygen atoms and stripping away electrons. The mineral is most abundant in soils that are seasonally waterlogged or poorly drained.
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Clues to Prion Infectivity
Structural Studies Reveal New Clues to Prion Infectivity
One of the unexplained questions facing prion researchers is how a single prion can apparently assume different conformations — with each conformation having different disease or phenotypic properties. Previous structural studies of prions had not yielded a clear understanding of the basis of strains because the prion protein is large and complex. Due to the size and complexity of prions, studies utilizing x-ray crystallography, a technique commonly used to determine the structure of proteins and other molecules, have been limited to short peptide fragments of the prion protein.
“There have been a number of fairly low-resolution pictures of prions that more or less proved that these different strains were in different conformations; but they really hadn’t established the nature of the different conformations,” Weissman said. “It was really a big black box. We basically didn’t have the conformation of any single prion, let alone the two prion protein strains in two different conformations.”
““In our minds, our findings brought to a certain level of closure the understanding of the structural differences underlying strains,” said Weissman. “Now we understand the structural differences. We also have an idea how those differences lead to the differences in physical properties, and, in turn, how these differences in the physical properties lead to the phenotypic differences. We are starting to go all the way from the structural understanding of the different strains up to in vivo understanding of why they cause different behaviors inside the cell.”
Weissman noted that the findings offer a broader lesson to researchers studying prions and other proteins whose misfolding can cause disease. “Certainly, a bottom line from this study is that the rules of protein folding and the rules of protein misfolding are fundamentally different,” he said. “In many ways, we have to relearn basic principles of how proteins misfold. We have to forget many of the rules we learned from textbooks about protein folding because they are not necessarily applicable.”
Prions are very interesting. Related posts: Scientists Knock-out Prion Gene in Cows – Gene Study Finds Cannibal Pattern – Open Access Education Materials on Protein Folding