Molecular Basis of Mammalian Prion Protein Misfolding


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Prions are aberrantly folded proteins that are able to self-propagate their abnormal conformation using the normally folded protein as substrate. In mammals, the only known prion protein is PrP. The misfolding of PrP is a key event underlying Transmissible Spongiform Encephalopaties (TSEs), fatal neurological disorders that affect many mammalian species. A self-propagating abnormally folded PrP is believed to be the essential component within the infectious agent, in what is called the protein-only hypothesis. Although the fundamental role of PrP in prion diseases has been settled after many years of research, the structural and mechanistic details of the conversion process leading to the infectious PrP conformation (PrPSc) is not yet elucidated. Moreover, the structure of the pathogenic entity is unknown and a crucial involvement of accessory molecules within the infectious particle has recently gained strong evidence. Prions have raised not only health-related concerns but also great interest from basic science due to their unusual features as pathogenic infectious agents. In order to gain insights into the molecular aspects featuring the PrP conversion process, I analyzed the role of PrP and potential accessory molecules on the formation of prion-like molecules. Under close-to-physiological conditions, I found that kosmotropic anions specifically modulate the formation of PrP aggregates with features reminiscent of PrPSc. I also studied the role of accessory molecules known to affect the conversion process. I found that the protease resistance of PrP aggregates, a well known biochemical hallmark of PrPSc, was highly dependent on the presence of hydrophobic and negatively charged molecules. Altogether, the results provide evidence toward the idea that the formation of prions is a synergistic event in which both PrP and accessory molecules are fundamental components.



Prion, misfolding, transmissible spongiform encephalopaties