Prion protein misfolding causes neurodegenerative disorders in humans and animals, such as cerebral amyloid angiopathy, Creutzfeldt-Jakob disease, kuru, “mad cow,” and scrapie. Previous studies have shown that the misfolded prion can function as an infectious agent capable of transmitting disease from one mammalian species to another, although the precise mechanisms remain unknown. In studying a prion model protein from three different species, a team from Ohio State University identifies key differences at the single amino acid level that contribute to distinct forms of prions.
Since 2008, the researchers have been doing solid-state structures of the prion protein variant that causes hereditary human cerebral amyloid angiopathy and have narrowed down the list of possibly critical amino acids to about 30. Now, in their newly published findings in Nature Communications, they have demonstrated that only two amino acid residues for the prion model "Y145Stop" largely control structural differences within species. Position 139 dictates whether the prion will adopt a human-like versus a hamster-like structure. Meanwhile, an amino acid at position 112 marks the difference between the human and mouse structures.
“The large-scale differences in the structures and transmission characteristics of these proteins—caused by what amounts to seemingly insignificant differences in the positions of a few carbon and hydrogen atoms—are quite remarkable,” said senior author Christopher Jaroniec.
Uncovering the molecular details of the prion protein is important because the prion's structure is believed to be critical to the protein's ability to be transmitted between different hosts. The team has discovered these molecular-level insights using solid-state nuclear magnetic resonance spectroscopy, a technique already well-established in studying amyloid structures in other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease.
“Our group is currently working on determining the high resolution molecular structures of the truncated prion protein variants associated with familial human CAA in order to gain a complete atomistic understanding of the factors underlying their transmission, and the present study is a major stepping stone in this effort,” Jaroniec said. “We hope that one day our group and other researchers will be able to use similar methodologies to unravel the structural basis of the transmissible prion diseases.”
Image: A molecular example of prion proteins aggregating into an amyloid complex. Image courtesy of RSCB PDB-101.