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United States Department of Agriculture

Agricultural Research Service

Title: Knocked-out and still walking: prion protein-deficient cattle are resistant to prion disease

item Richt, Juergen
item Hamir, Amirali
item Kuroiwa, Yoshimi - KIRIN PHARMA LTD
item Vargas, Francisco - UNIVER LISANDRO VENEZUELA
item Kunkle, Robert
item Schonenbrucher, Holger
item Kanthasamy, Anumantha - IOWA STATE UNIVERSITY

Submitted to: Meeting Abstract
Publication Type: Abstract Only
Publication Acceptance Date: August 22, 2008
Publication Date: August 22, 2008
Repository URL:
Citation: Richt, J.A., Hamir, A.N., Kuroiwa, Y., Vargas, F., Kunkle, R.A., Schonenbrucher, H., Kanthasamy, A., Robl, J.E. 2008. Knocked-out and still walking: prion protein-deficient cattle are resistant to prion disease [abstract]. Rocky Mountain Prion Research Symposium. Paper No. 10.

Technical Abstract: Background: Transmissible spongiform encephalopathies (TSEs) or prion diseases are caused by the propagation of a misfolded form (PrP**d) of the normal cellular prion protein, PrP**c. Disruption of PrP**c expression in the mouse results in resistance to PrP-propagation and disease. However, the impact of the ablation of PrP**c function in a natural host species of prion diseases is unknown. Recently, we have reported the generation and characterization of PrP**c deficient cattle (PrP-/-) produced by a sequential gene targeting system. Objectives: In this study we wanted to determine whether PrP-/- cattle are susceptible or resistant to prion diseases. Methods: Five PRNP+/+ wild-type and five PRNP-/- cattle were inoculated intracerebrally with a 10% brain homogenate derived from a bovine infected with a cattle-adapted TME isolate. Six other cattle (three each PRNP+/+ and PRNP-/-) were inoculated with normal brain material. Results: PRNP-/- cattle inoculated intracerebrally with a cattle-adapted transmissible mink encephalopathy (TME) isolate (i) do not replicate abnormal PrP**d in their central nervous system (CNS) for at least 23 months post inoculation (MPI) and (ii) are clinically normal at least 27 MPI. In contrast, all five PRNP+/+ cattle inoculated with TME were euthanized with clinical signs within 18 MPI and contained abnormal PrP**d in their CNS tissues. Discussion: Our results for the first time determine that PrP**c is a critical component in the pathogenesis of TSE disease of a natural host.

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