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The association between PrP and infectivity in scrapie and BSE infected mouse brain
1BBSRC & MRC Neuropathogenesis Unit, Institute for Animal Health, Edinburgh, U.K.
Abstract:
The structure of the scrapie agent remains unknown. However, scrapie infectivity tends to co-sediment with an infection specific fraction of the glycoprotein PrP (PrPSc) under conditions which solubilise the normal form of this protein (PrPc); accordingly, PrP has been proposed as a candidate component of the agent. To investigate this further we have been examining a new scrapie-related murine model in conjunction with established scrapie models. A bovine spongiform encephalopathy (BSE) derived murine model has short incubation periods, high infectivity titre and low amounts of PrP deposited in the brain. A membrane fraction from scrapie/BSE infected brain is solubilised with Sarkosyl at pH > or = 9.0. Most PrP is also solubilised. In models of the disease with little deposition of the PrP in the brain, this solubilisation step is particularly effective in reducing the amounts of PrP sedimented from brain extracts. Gradient centrifugation of the sedimented fraction shows further separation of infectivity and the residual PrP. It is concluded that at least some PrPSc in the brain need not be associated directly with infectious agents but is deposited in brain solely as a pathological product of infection. However, a residual sedimentable fraction contains PrP which may be a component of the agent.
Insights
Researchers investigated the scrapie agent's structure, finding that while some prion protein (PrPSc) deposits are pathological, a portion may be a component of the infectious agent itself.
Area of Science:
- Neuroscience
- Infectious Diseases
- Biochemistry
Background:
- The structure of the scrapie agent, responsible for transmissible spongiform encephalopathies, remains elusive.
- Prion protein (PrPSc) is implicated as a potential component of the scrapie agent, co-sedimenting with infectivity.
- Investigating PrPSc's role requires robust models to differentiate between pathological deposits and agent components.
Purpose of the Study:
- To investigate the association between prion protein (PrPSc) and scrapie infectivity.
- To determine if PrPSc is solely a pathological product or a component of the infectious agent.
- To characterize the scrapie agent using a bovine spongiform encephalopathy (BSE)-derived murine model.
Main Methods:
- Utilized a BSE-derived murine model with short incubation periods and high infectivity.
- Solubilized brain membrane fractions from infected animals using Sarkosyl at pH > or = 9.0.
- Employed gradient centrifugation to separate infectivity from residual PrP.
Main Results:
- Solubilization effectively reduced sedimented PrP in models with low PrP deposition.
- Gradient centrifugation revealed a separation between infectivity and residual PrP.
- A sedimentable fraction containing PrP was identified, potentially representing a component of the agent.
Conclusions:
- At least some PrPSc in the brain may represent pathological deposits, not directly associated with the infectious agent.
- A residual, sedimentable PrP fraction suggests a possible role as a component of the scrapie agent.
- Further research is needed to fully elucidate the scrapie agent's structure and PrP's definitive role.