Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.
The mechanisms involved in prion neurotoxicity are unclear, and therapies preventing accumulation of PrPSc, the disease-associated form of prion protein (PrP), do not significantly prolong survival in mice with central nervous system prion infection. We found that depleting endogenous neuronal PrPc in mice with established neuroinvasive prion infection reversed early spongiform change and prevented neuronal loss and progression to clinical disease. This occurred despite the accumulation of extraneuronal PrPSc to levels seen in terminally ill wild-type animals. Thus, the propagation of nonneuronal PrPSc is not pathogenic, but arresting the continued conversion of PrPc to PrPSc within neurons during scrapie infection prevents prion neurotoxicity.
Medical Research Council Prion Unit and Department of Neurodegenerative Disease, Institute of Neurology, Queen Square, London WC1, UK.
Giovanna
G
Mallucci
Andrew
A
Dickinson
Jacqueline
J
Linehan
Peter-Christian
PC
Klöhn
Sebastian
S
Brandner
John
J
Collinge
D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D001923:Brain Chemistry; D018450:Disease Progression; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D012608:Scrapie / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D019076:Transgenes
D018621:PrPC Proteins; D018620:PrPSc Proteins