Interactions between wild-type and mutant prion proteins modulate neurodegeneration in transgenic mice
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G C Telling1, T Haga, M Torchia
1Department of Neurology, University of California at San Francisco, 94143 USA.
Abstract:
Transgenic mice overexpressing approximately eightfold the mouse (Mo) prion protein (PrP) gene carrying the P102L mutation of GSS developed neurodegeneration between 150 and 300 days of age, while controls expressing the wild-type MoPrP-A transgene at the same level remained healthy. Mice overexpressing the wild-type MoPrP-A transgene were highly susceptible to inoculated mouse prions, exhibiting abbreviated scrapie incubation times of 45 days. After crossing the mutant transgene onto a null (Prnp 0/0) background, the resulting Tg(MoPrP-P101L)Prnp 0/0 mice displayed a highly synchronous onset of illness at 145 days of age, which was shortened to 85 days upon breeding to homozygosity for the transgene array. Besides occasional PrP plaques and modest spongiform degeneration, Tg(MoPrP-P101L) mice suffered from a myopathy and a peripheral neuropathy. Disruption of the wild-type MoPrP gene increased the number of PrP plaques and the severity of spongiform degeneration. Brain extracts prepared from spontaneously ill transgenic mice transmitted disease to Tg196/Prnp 0/0 mice, expressing low levels of the mutant transgene. Our results demonstrate that the presence of wild-type PrP genes, the level of PrP transgene expression, and the sequence of the transgene can profoundly modify experimental prion disease.
Insights
Transgenic mice with a GSS mutation in the prion protein (PrP) gene developed neurodegeneration. Modifying PrP gene expression and sequence significantly impacts prion disease progression and pathology.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- The prion protein (PrP) gene plays a crucial role in prion diseases.
- Gerstmann-Sträussler-Scheinker (GSS) syndrome is a familial prion disease linked to PrP mutations.
- Understanding how PrP mutations and expression levels influence disease pathogenesis is critical.
Purpose of the Study:
- To investigate the impact of a specific GSS-associated PrP mutation (P102L) on neurodegeneration in transgenic mice.
- To determine the influence of wild-type PrP gene presence, transgene expression levels, and transgene sequence on prion disease.
- To model GSS and analyze prion disease transmission.
Main Methods:
- Generation of transgenic mice overexpressing the mutant (P102L) mouse prion protein (MoPrP) transgene.
- Cross-breeding mutant PrP transgenic mice with PrP knockout (Prnp 0/0) mice.
- Assessing neurodegeneration, spongiform changes, PrP plaque formation, myopathy, and peripheral neuropathy.
- Transmission studies using brain extracts from affected transgenic mice.
Main Results:
- Mice overexpressing the P102L mutant PrP transgene developed neurodegeneration, while controls with wild-type PrP remained healthy.
- Reducing wild-type PrP gene dosage (Prnp 0/0 background) led to synchronous illness onset in mutant PrP mice.
- Homozygosity for the mutant transgene shortened illness onset.
- PrP plaque formation and spongiform degeneration severity were influenced by the presence of wild-type PrP genes.
- Transmissibility of the disease was demonstrated.
Conclusions:
- The presence of wild-type PrP genes, the level of PrP transgene expression, and the specific PrP transgene sequence profoundly modify experimental prion disease.
- The P102L mutation in PrP can induce neurodegeneration and associated pathologies.
- These findings provide insights into the complex interplay of genetic factors in prion disease pathogenesis.