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Strain-specified characteristics of mouse synthetic prions
Giuseppe Legname1, Hoang-Oanh B Nguyen, Ilia V Baskakov
1Institute for Neurodegenerative Diseases , University of California, San Francisco, CA 94143, USA.
Abstract:
Synthetic prions were produced in our laboratory by using recombinant mouse prion protein (MoPrP) composed of residues 89-230. The first mouse synthetic prion strain (MoSP1) was inoculated into transgenic (Tg) 9949 mice expressing N-terminally truncated MoPrP(Delta23-88) and WT FVB mice expressing full-length MoPrP. On first and second passage in Tg9949 mice, MoSP1 prions caused disease in 516 +/- 27 and 258 +/- 25 days, respectively; numerous, large vacuoles were found in the brainstem and gray matter of the cerebellum. MoSP1 prions passaged in Tg9949 mice were inoculated into FVB mice; on first and second passage, the FVB mice exhibited incubation times of 154 +/- 4 and 130 +/- 3 days, respectively. In FVB mice, vacuolation was less intense but more widely distributed, with numerous lesions in the hippocampus and cerebellar white matter. This constellation of widespread neuropatho-logic changes was similar to that found in FVB mice inoculated with Rocky Mountain Laboratory (RML) prions, a strain derived from a sheep with scrapie. Conformational stability studies showed that the half-maximal GdnHCl (Gdn1/2) concentration for denaturation of MoSP1 prions passaged in Tg9949 mice was approximately 4.2 M; passage in FVB mice reduced the Gdn1/2 value to approximately 1.7 M. RML prions passaged in either Tg9949 or FVB mice exhibited Gdn1/2 values of approximately 1.8 M. The incubation times, neuropathological lesion profiles, and Gdn1/2 values indicate that MoSP1 prions differ from RML and many other prion strains derived from sheep with scrapie and cattle with bovine spongiform encephalopathy.
Insights
Researchers created a synthetic prion strain (MoSP1) in the lab. This new prion strain, when passed through different mouse models, showed distinct incubation periods and brain damage patterns, differing from established prion strains.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Prion diseases are fatal neurodegenerative disorders caused by misfolded prion proteins.
- Understanding prion strain diversity is crucial for diagnosing and treating these diseases.
- Synthetic prions offer a tool to study prion biology and strain characteristics.
Purpose of the Study:
- To generate and characterize a novel synthetic prion strain (MoSP1) in a laboratory setting.
- To investigate the impact of host prion protein expression on MoSP1 prion propagation and pathogenesis.
- To compare the biological and biochemical properties of MoSP1 with a known prion strain (RML).
Main Methods:
- Production of recombinant mouse prion protein (MoPrP) and generation of synthetic prions (MoSP1).
- Inoculation of MoSP1 into transgenic mice expressing truncated MoPrP and wild-type FVB mice.
- Assessment of incubation times, neuropathological changes (vacuolation), and conformational stability (GdnHCl denaturation) of prion strains.
Main Results:
- MoSP1 induced disease with characteristic incubation times and distinct neuropathological profiles in both mouse models.
- Passage in FVB mice altered MoSP1's conformational stability, indicated by a lower GdnHCl denaturation concentration.
- MoSP1 exhibited different biological and biochemical properties compared to RML prions.
Conclusions:
- The synthetic prion strain MoSP1 demonstrates unique characteristics in terms of incubation period, lesion profile, and conformational stability.
- Host prion protein structure influences prion strain properties.
- MoSP1 represents a distinct prion strain that differs from established strains like RML.
