Vol 7. Issue 25 / September 10, 2007
Study Reveals Prion Disease Culprit
By Eric Sauter
Working in close collaboration with an international group of researchers, scientists at The Scripps Research Institute have shown for the first time that small clumps of abnormal prion proteins called oligomers cause the widespread death of neurons. In contrast, much larger prion aggregates known as fibrils proved to be far less toxic.
The findings suggest that small protein aggregates play a central role in prion diseases; similar mechanisms have been proposed for the so-called "amyloid" neurodegenerative diseases, including Alzheimer's. The work may provide novel therapeutic approaches for treating people with these conditions.
The study was published in the August 31, 2007, online edition of the journal PloS Pathogens.
"Our new study clearly establishes these misfolded prion protein oligomers as the major neurotoxic agent in both in vitro and in vivo experiments," said Professor Corinne Lasmézas, 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.
The Brain on Prions
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 found.
Mammalian cells normally produce what is known as cellular prion protein; during infection with a prion disease, though, the abnormal protein converts the normal host prion protein into a toxic form.
Oligomers are an intermediate aggregation state of the proteins, which start 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," Lasmézas 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 like the proteasome—the part of the cell designed to eliminate damaged or unwanted proteins. Old age brings with it an increased tendency for proteasome dysfunction and protein damage or misfolding, which could explain the increase in amyloid diseases in later life.
Preventing Neuron Death
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 control cells, a level considered highly toxic.
The study's results also showed that exposure of a specific surface region of the prion protein oligomer was required to initiate 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 inhibit neuronal toxicity," she said. "This region represents a very good therapeutic target, but there may be other target regions as well."
The scientists' in vivo findings with mouse 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," Lasmézas said. "The degree of this commonality is remarkable, and our findings open new avenues for the development of neuroprotective strategies that directly target toxic prion oligomers."
Other authors of the study, "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 Schätzl of the Institute of Virology, Germany; Nicole Sales of The Scripps Research Institute; Maxime Lefebvre-Roque of the Commissariat à l'Energie Atomique and The Scripps Research Institute; and Catherine Vidal of the Institut Pasteur, France. For the article, see http://pathogens.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.ppat.0030125.
The study was supported by the European Union, the NeuroPrion Network of Excellence, and the German Science Foundation.
Send comments to: mikaono[at]scripps.edu