Scientists from the Florida campus of The Scripps Research Institute have identified a single prion protein that causes neuronal death similar to that seen in “mad cow” disease, but which is at least 10 times more lethal than larger prion species. This toxic single molecule or “monomer” challenges the prevailing concept that neuronal damage is linked to the toxicity of prion protein aggregates called “oligomers.” The study was published online on February 7, 2012 in PNAS. “By identifying a single molecule as the most toxic species of prion proteins, we’ve opened a new chapter in understanding how prion-induced neurodegeneration occurs,” said Scripps Florida Professor Corinne Lasmézas, who led the new study. “We didn’t think we would find neuronal death from this toxic monomer so close to what normally happens in the disease state. Now we have a powerful tool to explore the mechanisms of neurodegeneration.” In the study, the newly identified toxic form of abnormal prion protein, known as TPrP, caused several forms of neuronal damage ranging from apoptosis (programmed cell death) to autophagy, the self-eating of cellular components, as well as molecular signatures remarkably similar to that observed in the brains of prion-infected animals. The study found the most toxic form of prion protein was a specific structure described as alpha-helical. In addition to the insights it offers into prion diseases such as “mad cow” and a rare human form called Creutzfeldt-Jakob disease, the study opens the possibility that similar neurotoxic proteins might be involved in neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. In prion disease, infectious prions (short for proteinaceous infectious particles), thought to be composed solely of protein, have the ability to reproduce, despite the fact that they lack DNA and RNA.
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