PrP and amyloidosis

PrP and Amyloidosis. In collaboration with Simon Sharpe (Sick Kids Hospital & UofT), we are examining the phenomenon of aggregation and amyloidosis of a prion protein, which is prepared in an aggregation prone beta-state. Prion diseases are rapidly progressive, fatal and untreatable neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD), fatal familiar insomnia (FFI) and kuru in humans. NMR studies reveal a distinct equilibrium consisting of monomer, octamer, and what we believe is a prefibrillar aggregate. These components are in exchange on an NMR timescale and a temperature and pressure dependence of this equilibrium provides a thermodynamic perspective of the driving forces associated with the aggregation pathway.

PrP  exchangePrP populations

Figure 2. Model for exchange between assembled states within ShaPrP(90-231)β. The exchange processes observed between β-monomer, β-octamer, and larger oligomers of ShaPrP(90-231) are indicated by arrows connecting the different species. The relative fractions of each state at 28°C and ambient pressure are shown for WT (blue) and the F198S mutant (red), while estimated exchange rates are indicated on the arrows between states.

We recently identified a way of delineating the alpha state and it’s conversion to the beta states. This gives us for the first time to study the action of drugs and cell players in terms of mechanisms of amyloidosis and pharmacological agents to mediate the process:

PrP Cascade

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