Different behavior toward bovine spongiform encephalopathy infection of bovine prion protein transgenic mice with one extra repeat octapeptide insert mutation

被引:47
作者
Castilla, J
Gutiérrez-Adán, A
Brun, A
Pintado, B
Parra, B
Ramírez, MA
Salguero, FJ
San Segundo, FD
Rábano, A
Cano, MJ
Torres, JM
机构
[1] Natl Inst Agr Technol & Invest, Ctr Anim Hlth Invest, Madrid 28130, Spain
[2] Dept Anim Reprod, Madrid, Spain
[3] Zoogenet Resources Conservat, Madrid, Spain
[4] Alcorcon Hosp, Neuropathol Lab, Madrid 28922, Spain
关键词
BSE transmission; transgenic mice; prion; octapeptide repeats; bioassay; scrapie; PrP;
D O I
10.1523/JNEUROSCI.3811-03.2004
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In humans, insert mutations within the repetitive octapeptide region of the prion protein gene (Prnp) are often associated with familial spongiform encephalopathies. In this study, transgenic mice expressing bovine PrP (boTg mice) bearing an additional octapeptide insertion to the wild type (seven octapeptide repeats instead of six) showed an altered course of bovine spongiform encephalopathy (BSE) infection, reflected as reduced incubation times when compared with boTg mice expressing similar levels of the wild-type six-octapeptide protein. In both boTg mouse lines (bo6ORTg and bo7ORTg), incubation times were affected drastically depending on transgene expression levels and the inoculum used. In accordance with the lack of an interspecies barrier to BSE infection, we detected the typical signs of CNS spongiform degeneration by histopathological analysis and the presence of the bovine prion PrPres by Western blot or immunohistochemical analyses. When 7OR-PrPres was propagated in bo7ORTg mice, a similar earlier onset of clinical signs was observed compared with bo6ORTg mice. Proteins PrPC and PrPres containing seven octapeptides (7OR-PrPC and 7OR-PrPres) showed similar protease sensitivity and insolubility in nondenaturing detergents to homologous 6OR-PrPC and 6OR-PrPres. In addition, bo7ORTg mice showed a higher sensitivity than bo6ORTg mice for detecting prion infection in specimens previously diagnosed as negative by conventional biochemical techniques. In the absence of clinical signs of disease, 7OR-PrPres could be detected as early as 120 d after inoculation by immunohistochemical and Western blot analyses. These findings may help us improve the current mouse bioassays and understand the role of the octapeptide repeat region in susceptibility to disease.
引用
收藏
页码:2156 / 2164
页数:9
相关论文
共 46 条
[1]   THE NATURE OF THE SCRAPIE AGENT [J].
ADAMS, DH .
MEDICAL HYPOTHESES, 1986, 20 (01) :37-50
[2]  
ALPERS M, 1971, Proceedings of the Australian Association of Neurologists, V8, P7
[3]   CREUTZFELDT-JAKOB DISEASE - NEUROPATHOLOGY OF A TRANSMISSION EXPERIMENT [J].
BECK, E ;
DANIEL, PM ;
MATTHEWS, WB ;
STEVENS, DL ;
ALPERS, MP ;
ASHER, DM ;
GAJDUSEK, DC ;
GIBBS, CJ .
BRAIN, 1969, 92 :699-&
[4]   Two-octapeptide repeat deletion of prion protein associated with rapidly progressive dementia [J].
Beck, JA ;
Mead, S ;
Campbell, TA ;
Dickinson, A ;
Wientjens, DPMW ;
Croes, EA ;
Van Duijn, CM ;
Collinge, J .
NEUROLOGY, 2001, 57 (02) :354-356
[5]   THE HUMAN SPONGIFORM ENCEPHALOPATHIES [J].
BENDHEIM, PE .
NEUROLOGIC CLINICS, 1984, 2 (02) :281-298
[6]   A vector for expressing foreign genes in the brains and hearts of transgenic mice [J].
Borchelt, DR ;
Davis, J ;
Fischer, M ;
Lee, MK ;
Slunt, HH ;
Ratovitsky, T ;
Regard, J ;
Copeland, NG ;
Jenkins, NA ;
Sisodia, SS ;
Price, DL .
GENETIC ANALYSIS-BIOMOLECULAR ENGINEERING, 1996, 13 (06) :159-163
[7]   Proteinase K enhanced immunoreactivity of the prion protein-specific monoclonal antibody 2A11 [J].
Brun, A ;
Castilla, J ;
Ramírez, MA ;
Prager, K ;
Parra, B ;
Salguero, FJ ;
Shiveral, D ;
Sánchez, C ;
Sánchez-Vizcaíno, JM ;
Douglas, A ;
Torres, JM .
NEUROSCIENCE RESEARCH, 2004, 48 (01) :75-83
[8]   A prion disease with a novel 96-base pair insertional mutation in the prion protein gene [J].
Campbell, TA ;
Palmer, MS ;
Will, RG ;
Gibb, WRG ;
Luthert, PJ ;
Collinge, J .
NEUROLOGY, 1996, 46 (03) :761-766
[9]   Familial prion disease with a novel 144-bp insertion in the prion protein gene in a Basque family [J].
Capellari, S ;
Vital, C ;
Parchi, P ;
Petersen, RB ;
Ferrer, X ;
Jarnier, D ;
Pegoraro, E ;
Gambetti, P ;
Julien, J .
NEUROLOGY, 1997, 49 (01) :133-141
[10]   Early detection of PRPres in BSE-infected bovine PrP transgenic mice [J].
Castilla, J ;
Adán, AG ;
Brun, A ;
Pintado, B ;
Ramírez, MA ;
Parra, B ;
Doyle, D ;
Rogers, M ;
Salguero, FJ ;
Sánchez, C ;
Sánchez-Vizcaíno, JM ;
Torres, JM .
ARCHIVES OF VIROLOGY, 2003, 148 (04) :677-691