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Prion clearance in bigenic mice
Jiri G Safar1,2, Stephen J DeArmond3,2, Katarzyna Kociuba2
1Department of Neurology, University of California, 513 Parnassus Ave, San Francisco, CA 94143, USA.
Abstract:
The clearance of prions from the brain was investigated in bigenic mice designated Tg(tTA : PrP(+/0))3, in which expression of the cellular prion protein (PrP(C)) was regulated by oral doxycycline administration. With suppression of PrP(C) expression, the incubation time for RML prions was prolonged almost threefold from approximately 150 to approximately 430 days. To determine the clearance rate of disease-causing PrP(Sc), bigenic mice were given oral doxycycline beginning 98 days after inoculation with RML prions and sacrificed at various time points over the subsequent 56 days. The half-life (t1/2) for PrP(Sc) was approximately 1.5 days in mouse brain, in reasonable agreement with the apparent t1/2 of 30 h that was determined in a separate study for scrapie-infected mouse neuroblastoma (ScN2a) cells in culture. Both protease-sensitive and -resistant conformers of PrP(Sc) were cleared at the same rate. The t1/2 value for PrP(C) clearance from brain was approximately 18 h, which was considerably longer than the t1/2 of 5 h found in ScN2a cells. The capability of the brain to clear prions raises the possibility that PrP(Sc) is normally made at low levels and continually cleared, and that PrP(Sc) may have a function in cellular metabolism. Moreover, these bigenic mice make it possible to determine both components of PrP(Sc) accumulation, i.e. the rates of formation and clearance, for various strains of prions exhibiting different incubation times.
Insights
Prion (PrPSc) clearance from the brain was studied in genetically modified mice. Prion protein (PrPC) suppression extended incubation times, and PrPSc clearance had a half-life of approximately 1.5 days in the brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Prion Disease Research
Background:
- Prion diseases are associated with the accumulation of misfolded prion protein (PrPSc).
- Understanding prion clearance mechanisms is crucial for developing therapeutic strategies.
- Cellular prion protein (PrPC) expression levels influence prion disease progression.
Purpose of the Study:
- To investigate the clearance rate of prions (PrPSc) from the brain in vivo.
- To determine the half-life of PrPSc in the brain of bigenic mice.
- To compare the clearance rates of PrPSc and PrPC in the brain.
Main Methods:
- Utilized bigenic mice (Tg(tTA : PrP(+/0))3) with doxycycline-regulated PrPC expression.
- Suppressed PrPC expression using oral doxycycline administration post-RML prion inoculation.
- Quantified PrPSc and PrPC levels at various time points to determine clearance rates and half-lives.
Main Results:
- Suppression of PrPC expression prolonged RML prion incubation time nearly threefold.
- The half-life (t1/2) of PrPSc in mouse brain was determined to be approximately 1.5 days.
- PrPC clearance from the brain had a t1/2 of approximately 18 hours, longer than in cultured cells.
Conclusions:
- The brain possesses a capability to clear prions (PrPSc), suggesting a potential physiological role for PrPSc.
- Bigenic mouse models allow for the independent determination of PrPSc formation and clearance rates.
- This research provides a foundation for studying prion accumulation dynamics for different prion strains.
