Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease

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Genetic prion diseases are degenerative brain disorders caused by mutations in the gene encoding the prion protein (PrP). Different PrP mutations cause different diseases, including Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI). The reason for this variability is not known, but assembly of the mutant PrPs into distinct aggregates that spread in the brain by promoting PrP aggregation may contribute to the disease phenotype. We previously generated transgenic mice modeling genetic CJD, clinically identified by dementia and motor abnormalities. We have now generated transgenic mice carrying the PrP mutation associated with FFI, and found that they develop severe sleep abnormalities and other key features of the human disorder. Thus, transgenic mice recapitulate the phenotypic differences seen in humans. The mutant PrPs in FFI and CJD mice are aggregated but unable to promote PrP aggregation. They accumulate in different intracellular compartments and cause distinct morphological abnormalities of transport organelles. These results indicate that mutant PrP has disease-encoding properties that are independent of its ability to self-propagate, and suggest that the phenotypic heterogeneity may be due to different effects of aggregated PrP on intracellular transport. Our study provides new insights into the mechanisms of selective neuronal dysfunction due to protein aggregation.

Vyšlo v časopise: Transgenic Fatal Familial Insomnia Mice Indicate Prion Infectivity-Independent Mechanisms of Pathogenesis and Phenotypic Expression of Disease. PLoS Pathog 11(4): e32767. doi:10.1371/journal.ppat.1004796
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004796

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