NR ATFI
AU Chiesa,R.; Dossena,S.; Mangieri,M.; Balducci,C.; Bianchi,S.; Fioriti,L.; Carli,M.; Tagliavini,F.; Imeri,L.; Forloni,G.
TI Transgenic Mice Expressing the Polymorphic Variants of the PrP D178N Mutation Recapitulate the Phenotypic Variability of Inherited Prion Diseases
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Oral sessions ORAL-13
PT Konferenz-Vortrag
AB Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob disease (CJD178) are clinically and neuropathologically distinct diseases linked to the D178N mutation in the gene encoding the prion protein (PrP). The disease phenotype is determined by the M/V polymorphism at codon 129 of the mutant allele: D178N/M129 segregates with FFI, while D178N/V129 is associated with CJD178. We have generated transgenic (Tg) mice that express the mouse PrP homologues of these mutations (D177N/M128 and D177N/V128). We found that both mutants acquired biochemical properties reminiscent of PrPsc, the pathogenic isoform of PrP, including detergent insolubility and low protease resistance. Immunohistochemical analyses revealed gliosis and PrP deposition in the hippocampus, neocortex, and cerebellum. A progressive neurological disorder was observed in Tg(D177N/V128) mice that express the mutant protein at physiological level, but not in mice with lower expression level. The primary symptoms of this disorder include clasping of the hind limbs, ataxia, and kyphosis. A similar, although less severe disease phenotype was observed in Tg(D177N/M128) mice. These mice, however, showed also significant alterations of the circadian rhythms and sleep patterns, including increased number of horizontal movements during the transition from the dark to the light cycle, as well as dramatic reduction of non-REM and REM sleep. Significant increase of locomotor activity in the 24 h and reduced REM sleep were observed also in aged Tg(D177N/V128) mice. No alterations were found in non-transgenic littermates or Tg(WT) controls. These results indicate that the Tg(D177N) mice faithfully reproduce key biochemical, neuropathological and clinical features of FFI and CJD178. This is the first time that the phenotypic heterogeneity determined by the M/V polymorphism associated with a PrP mutation has been modeled in Tg mice.
AD Roberto Chiesa, Sara Dossena, Luana Fioriti, Dulbecco Telethon Institute, Milan, Italy; Roberto Chiesa, Sara Dossena, Claudia Balducci, Luana Fioriti, Mirjana Carli, Gianluigi Forloni, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy; Michela Mangieri, Fabrizio Tagliavini, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy; Susanna Bianchi, Luca Imeri, Istituto di Fisiologia Umana II, University of Milan, Milan, Italy
SP englisch
PO Deutschland