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Genetics of prion diseases and prion diversity in mice
G A Carlson1, S J DeArmond, M Torchia
1McLaughlin Research Institute, Great Falls, Montana 59405.
Abstract:
Linkage of the prion protein (PrP) and scrapie incubation time genes in mice provided strong evidence for the central role of PrP in determining susceptibility to prion disorders. Considerable evidence now argues that the prion protein and incubation time genes are identical. The mouse prion protein gene (Prn-p) may act both quantitatively and qualitatively in modulating prion incubation time. Differences at positions 108 and 189 between PrP-A and PrP-B allotypes can place constraints on interaction between the normal cellular and the scrapie-specific isoforms of PrP (PrPC and PrPSc), although the supply of PrPC available for post-translational conversion to PrPSc can also influence incubation time. Results using transgenic (Tg) mice in studies on scrapie 'strains' or isolates suggest that incubation time characteristics of scrapie isolates can be explained by these two properties of PrP. The final section of this report discusses the novel finding that uninoculated Tg mice overexpressing wild-type (wt) PrP transgenes spontaneously develop a late-onset degenerative neuromyopathy, broadening the spectrum of prion diseases and providing new information on PrP function in both normal and pathological states.
Insights
The prion protein (PrP) gene influences prion disorder susceptibility and incubation times in mice. Overexpressing PrP in transgenic mice caused spontaneous degenerative neuromyopathy, revealing new insights into PrP function.
Area of Science:
- Neuroscience
- Genetics
- Biochemistry
Background:
- Prion protein (PrP) gene linkage to scrapie incubation time suggests PrP's central role in prion disorder susceptibility.
- Evidence indicates the prion protein and incubation time genes are identical, with Prn-p acting quantitatively and qualitatively.
Purpose of the Study:
- To investigate the role of PrP gene allotypes in modulating prion incubation time.
- To explore how PrP structure and expression levels influence prion disease pathogenesis.
- To examine spontaneous neurodegenerative conditions in PrP-overexpressing transgenic mice.
Main Methods:
- Analysis of prion protein (PrP) gene linkage and allotypes (PrP-A, PrP-B) in mice.
- Studies using transgenic (Tg) mice overexpressing wild-type (wt) PrP.
- Observation and characterization of scrapie isolates and their incubation time characteristics.
Main Results:
- PrP gene allotypic differences at positions 108 and 189 constrain PrPC-PrPSc interactions, affecting incubation time.
- The supply of PrPC influences post-translational conversion to PrPSc and incubation time.
- Transgenic mice overexpressing wt PrP developed spontaneous late-onset degenerative neuromyopathy.
Conclusions:
- PrP structure and expression are key determinants of prion disease incubation time and susceptibility.
- PrP plays a critical role in normal physiological function, as evidenced by spontaneous neurodegeneration in Tg mice.
- These findings broaden the understanding of prion diseases and PrP function in health and disease.