The findings declare that small protein aggregates compete a central role in prion diseases; similar mechanisms have been proposed for the so-called "amyloid" neurodegenerative diseases including Alzheimer's. The bring home the bacon may give novel therapeutic approaches for treating populate with these conditions.
"Our new chew over clearly establishes these misfolded prion protein oligomers as the major neurotoxic agent in both in vitro and in vivo experiments," said Professor Corinne Lasm⁄zas a Scripps Research scientist in the Florida campus's Department of Infectology who led the study. "This new discovery reveals the most likely culprit responsible for the death of neurons associated with spongiform encephalopathies and probably other neurodegenerative diseases."
The researchers posit that prion oligomers damage neurons by disturbing neuronal membranes and hence cell signaling as well as by building up excessively within cells eventually triggering apoptotic or programmed cell death.
Infectious prions (short for proteinaceous infectious particles) are unique pathogens associated with some 20 different diseases in humans and other animals including mad cow disease and a rare human form. Creutzfeldt-Jacob disease. Prions thought to be composed solely of protein have the ability to reproduce despite the fact that no nucleic acid genome has yet been open.
Mammalian cells normally produce what is known as cellular prion protein; during infection with a prion disease though the abnormal protein converts the normal entertain prion protein into a toxic create.
Oligomers are an negociate aggregation express of the proteins which go away out as individual molecules or monomers. The fibril end-stage consists of much larger clumps or sheets (polymers) of proteins.
"When we look at the brain of an individual or an animal affected by a prion disease," Lasm⁄zas noted. "we don't find neurons dying in the same region as large fibril deposits (also called plaques). One theory suggests that these large fibril deposits may actually be the brain's way of containing the toxicity of the intermediate-stage oligomers."
Toxic proteins are instead likely to accumulate in intracellular degradation pathways desire the proteasome—the move of the cell designed to eliminate damaged or unwanted proteins. Old age brings with it an increased tendency for proteasome dysfunction and protein alter or misfolding which could inform the change magnitude in amyloid diseases in later life.
In the new study the scientists first analyzed the neurotoxic properties of prion protein oligomers in neuronal cultures. Exposure of these neurons to prion protein oligomers resulted in a loss of nearly 50 percent of the neurons when compared to the untreated hold back cells a aim considered highly toxic.
The study's results also showed that exposure of a specific ascend region of the prion protein oligomer was required to create this common neurotoxic mechanism; antibodies that recognized this region were able to inhibit cellular toxicity and prevent neuronal death.
"In our in vitro studies there was a dramatic antibody effect—if you block this region of the oligomers you completely check neuronal toxicity," she said. "This region represents a very good therapeutic aim but there may be other target regions as come up."
The scientists' in vivo findings with walk models supported the picture that small prion aggregates rather than plaque-type prion deposits were responsible for neuronal dysfunction and death.
"Our new work demonstrates that the prion-induced neurodegeneration mechanism we uncovered in prion diseases is similar to that of other diseases such as Alzheimer's. Huntington's and Parkinson's," Lasm⁄zas said. "The degree of this commonality is remarkable and our findings change state new avenues for the development of neuroprotective strategies that directly aim toxic prion oligomers."
Other authors of the chew over. "In Vitro and In Vivo Neurotoxicity of Prion Protein Oligomers," include Steve Simoneau. Jean-Guy Fournier and Julien Comte of the Commissariat a` l'Energie Atomique. France; Human Rezaei and Jeanne Grosclaude of the Institut National de la Recherche Agronomique. France; Gunnar Kaiser-Schulz. Franziska Wopfner and Hermann Sch…tzl of the Institute of Virology. Germany; Nicole Sales of The Scripps investigate Institute; Maxime Lefebvre-Roque of the Commissariat √ l'Energie Atomique and The Scripps Research Institute; and Catherine Vidal of the Institut Pasteur. France.
The chew over was published in the August 31. 2007 online edition of the journal PloS Pathogens. (doi=10.1371/journal ppat.0030125)
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http://science.originalsignal.com/article/32153/small-clumps-of-prion-proteins-may-be-primary-cause-of-neurodegenerative-diseases.html
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