Methionine oxidation within the prion protein.

Abstract

Prion diseases are characterized by the self-templated misfolding of the cellular prion protein (PrP^C) into infectious aggregates (PrP^Sc). The detailed molecular basis of the misfolding and aggregation of PrP^C remains incompletely understood. It is believed that the transient misfolding of PrP^C into partially structured intermediates precedes the formation of insoluble protein aggregates and is a critical component of the prion misfolding pathway. A number of environmental factors have been shown to induce the destabilization of PrP^C and promote its initial misfolding. Recently, oxidative stress and reactive oxygen species (ROS) have emerged as one possible mechanism by which the destabilization of PrP^C can be induced under physiological conditions. Methionine residues are uniquely vulnerable to oxidation by ROS and the formation of methionine sulfoxides leads to the misfolding and subsequent aggregation of PrP^C. Here, we provide a review of the evidence for the oxidation of methionine residues in PrP^C and its potential role in the formation of pathogenic prion aggregates.