NR ATQA
AU Dossena,S.; Fioriti,L.; Mangieri,M.; Balducci,C.; Bianchi,S.; Carli,M.; Imeri,L.; Tagliavini,F.; Forloni,G.; Chiesa,R.
TI The Mouse Homologues of the Human D178N/M129 and D178N/V129 PrP Mutations Linked to Fatal Familial Insomnia and Familial Creutzfeldt-Jakob Disease Display Different Molecular Properties and Produce Distinct Disease Phenotypes in Transgenic Mice
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Pathogenesis PATH-37
PT Konferenz-Poster
AB The M/V polymorphism at codon 129 of the prion protein (PrP) profoundly affects the clinical presentation of an inherited prion disease due to the D178N mutation. The D178N/V129 allele segregates with familial Creutzfeldt-Jakob disease (CJD178) recognized clinically by dementia and motor abnormalities, while D178N/M129 segregates with fatal familial insomnia (FFI), characterized by alteration of sleep and endocrine dysfunction. Specific biochemical and neuropathological features accompany these clinical differences: distinct PK-resistant PrP isoforms are found in CJD178 and FFI brains, associated with different patterns of PrP deposition. We have engineered transgenic (Tg) mice to express mouse PrP homologues of the D178N/V129 and D178N/M129 mutations. cDNAs encoding 3F4-tagged mouse PrP D177N/V128 or D177N/M128 under the control of the mouse PrP promoter were injected into fertilized eggs from C57BL/6J x CBA/J mice, and the Tg founders were backcrossed to PrP knockout mice. The Tg mice expressing mutant PrPs at physiological levels developed distinct disease phenotypes with the essential clinical features of CJD178 and FFI. In particular, Tg(D177N/V128) showed a neurological syndrome characterized primarily by motor dysfunction, while Tg(D177N/M128) mice exhibited dramatic alterations of circadian rhythms and sleep patterns. Biochemical analyses revealed that both mutants were detergent insoluble, and partially resistant to digestion with low concentrations of proteinase K. However, D177N/V128 PrP displayed higher resistance to urea-induced disaggregation and to protease digestion than D177N/M128 PrP. Immunohistochemical analysis of the brain revealed higher amounts of PK-resistant PrP in Tg(D177N/V128) mice than in Tg(D177N/M128) animals. These data indicate that D177N/V128 and D177N/M128 differ in their structural state, and provide a direct link between the molecular properties of PrP and the phenotypic variability of inherited prion diseases.
AD Sara Dossena, Luana Fioriti, Roberto Chiesa, Dulbecco Telethon Institute, Milan, Italy; Sara Dossena, Luana Fioriti, Claudia Balducci, Mirjana Carli, Gianluigi Forloni, Roberto Chiesa, 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