De novo generation of a transmissible spongiform encephalopathy by mouse transgenesis.
Most transmissible spongiform encephalopathies arise either spontaneously or by infection. Mutations of PRNP, which encodes the prion protein, PrP, segregate with phenotypically similar diseases. Here we report that moderate overexpression in transgenic mice of mPrP(170N,174T), a mouse PrP with two point mutations that subtly affect the structure of its globular domain, causes a fully penetrant lethal spongiform encephalopathy with cerebral PrP plaques. This genetic disease was reproduced with 100% attack rate by intracerebral inoculation of brain homogenate to tga20 mice overexpressing WT PrP, and from the latter to WT mice, but not to PrP-deficient mice. Upon successive transmissions, the incubation periods decreased and PrP became more protease-resistant, indicating the presence of a strain barrier that was gradually overcome by repeated passaging. This shows that expression of a subtly altered prion protein, with known 3D structure, efficiently generates a prion disease.
Sigurdson
Christina J
CJ
UniversitätsSpital Zürich, Institute of Neuropathology, CH-8091 Zürich, Switzerland.
Nilsson
K Peter R
KP
Hornemann
Simone
S
Heikenwalder
Mathias
M
Manco
Giuseppe
G
Schwarz
Petra
P
Ott
David
D
Rülicke
Thomas
T
Liberski
Pawel P
PP
Julius
Christian
C
Falsig
Jeppe
J
Stitz
Lothar
L
Wüthrich
Kurt
K
Aguzzi
Adriano
A
D000818:Animals; D018014:Gene Transfer Techniques; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D017096:Prion Diseases / Q000209:etiology* / Q000473:pathology / Q000635:transmission; D011328:Prions / Q000008:administration & dosage / Q000235:genetics*; D011487:Protein Conformation
D011328:Prions