NR AWKJ
AU Moleres,F.J.; Richardson,S.; Velayos,J.L.; Kong,Q.; Zou,W.Q.; Gambetti,P.; Petersen,R.B.
TI De novo generation of protease-resistant prion protein in transgenic mice mimicking fatal familial insomnia
QU International Conference - Prion 2006: Strategies, advances and trends towards protection of society - 3.10.-6.10.2006, Torino, Italy, Lingotto Conference Centre - Poster sessions PR-22
PT Konferenz-Poster
AB Fatal familial insomnia (FFI) is produced by the aspartic acid to asparagine substitution at codon 178 (D178N) of the gene that encodes the prion protein (PrP). This mutation is coupled to methionine at codon 129 (129M), a common polymorphic site in the prion protein gene. We have analyzed the PrP characteristics together with the levels of expression of some other markers differently involved in FFI in a line of transgenic mice with the equivalent genetic background to that present in human FFI [Tg(MoPrP-D177N/128M) or Tg(FFI)]. We have found that, when compared to control animals [wt and Tg(MoPrP-128M)], Tg(FFI) showed a striking under-representation of the unglycosylated forms of PrP and resistance to digestion by proteases. The protease resistance was prominent in old mice, where the levels of resistance were comparable to those used for diagnostic procedures in human subjects. The size of the protease resistant core of PrP was 19 kDa, equivalent to that present in human FFI (type 2-PrPsc). The accumulation of abnormally-folded mutant PrP in Tg(FFI) is the most likely cause for all these features. Additionally, and as observed in human FFI patients, we noted an alteration of both the serotoninergic and orexinergic systems while the levels of parvalbumin were normal. The present findings suggest that Tg(FFI) reproduce at least some of the FFI pathogenetic mechanisms making Tg(FFI) a suitable tool for the study of this disease. Supported by NIH grant AG14359; CDC Grant CCU 515004 and the Britton Fund. FJM is supported by a FPU grant 2003-5033.
AD F.J. Moleres: Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA and Department of Anatomy, Universidad de Navarra, Pamplona, Spain; S. Richardson, Q. Kong, W.-Q. Zou, P. Gambetti, R.B. Petersen: Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA; J.L. Velayos: Department of Anatomy, Universidad de Navarra, Pamplona, Spain
SP englisch
PO Italien