|
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.
Researchers previously generated transgenic mice
modeling genetic CJD, clinically identified by
dementia and motor abnormalities. They 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. This study provides new insights into the
mechanisms of selective neuronal dysfunction due to
protein aggregation.
For more information
PLOS Pathogens
Transgenic Fatal Familial Insomnia Mice Indicate
Prion Infectivity-Independent Mechanisms of
Pathogenesis and Phenotypic Expression of Disease
Ihssane Bouybayoune, Susanna Mantovani, Federico Del
Gallo, Ilaria Bertani, Elena Restelli, Liliana
Comerio, Laura Tapella, Francesca Baracchi, Natalia
Fernández-Borges, Michela Mangieri, Cinzia Bisighini,
Galina V. Beznoussenk, Alessandra Paladini, Claudia
Balducci, Edoardo Micotti, Gianluigi Forloni,
Joaquín Castilla, Fabio Fiordaliso, Fabrizio
Tagliavini, Luca Imeri, and Roberto Chiesa
http://dx.plos.org/10.1371/journal.ppat.1004796.
MDN |