From The Scientist
November 3, 2003
Preventing prion disease progressionDepletion of neuronal prion proteins after scrapie prion infection prevents disease development | By David Secko
Diseases characterized by pathological prion proteins (PrPSc) are neurodegenerative and ultimately fatal. The underlying cause of the disease is linked to a pathological progression that sees host prion proteins (PrPc) converted to PrPScs, followed by extensive neuronal loss. No treatment exists to prevent the progression of the disease during central nervous system (CNS) infection, and the cause of neuronal death is still unclear. In the October 31 Science, Giovanna Mallucci and colleagues from the Institute of Neurology report that the reduction of PrPc in mouse neurons after prion infection prevents progression of the disease and allows the mice to survive (Science, 302:871-874, October 31, 2003).
Mallucci et al. have shown that depletion of neuronal PrPc adult mice was not damaging, and they used this observation to test the effect of PrPc depletion on mice infected with disease-causing Rocky Mountain Laboratories scrapie prions. They used the Cre-Lox system to restrict the depletion of PrPc to neurons after 10 to 12 weeks of age. Mice that had been infected at 3 to 4 weeks old showed pathological evidence of scrapie infection at 8 weeks, but as neuronal PrPc was depleted in the subsequent weeks, the mice did not progress to a clinical prion disease and survived; control mice died 4 to 8 weeks later. In addition, early intraneuronal vacuoles indicative of developing spongiosis were reversed in scrapie-infected mice with depleted PrPc. Infected animals still showed some PrPSc deposition, which was attributed to scrapie replication in cells not expressing Cre (e.g., astrocytes). The authors conclude that clinical progression of the disease does not rely on extensive PrPSc deposition in the model used, suggesting that the conversion of “PrPc to disease-associated isoform” was toxic to neurons.
“We have demonstrated an intervention that prevents the development of symptomatic prion disease in mice with established CNS scrapie infection,” conclude the authors. They point to PrPc as a therapeutic target that could ultimately prevent progression of clinical prion diseases.
Links for this article
S.J. DeArmond, E. Bouzamondo, “Fundamentals of prion biology and diseases,” Toxicology, 181-182:9-16, December 27, 2002.
[PubMed Abstract]
H. Bueler et al., “Mice devoid of PrP are resistant to scrapie,” Cell, 73:1339-1347, July 2, 1993.
[PubMed Abstract]
G. Mallucci et al., “Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis,” Science, 302:871-874, October 31, 2003.
sciencemag.org
Institute of Neurology
ion.ucl.ac.uk
G.R. Mallucci et al., “Post-natal knockout of prion protein alters hippocampal CA1 properties, but does not result in neurodegeneration,” EMBO Journal, 21:202-210, February 1, 2002. |
