NR ATPH
AU Biasini,E.; Rossi,V.; Massignan,T.; Fioriti,L.; Dossena,S.; Salmona,M.; Forloni,G.; Bonetto,V.; Chiesa,R.
TI Analysis of the Cerebellar Proteome in a Transgenic Mouse Model of an Inherited Prion Disease Reveals Preclinical Alteration of Calcineurin Activity
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Pathogenesis PATH-18
PT Konferenz-Poster
AB Tg(PG14) mice express a mutant prion protein containing 14 octapeptide repeats, whose human homologue is associated with an inherited prion disease. These mice develop a progressive neurological disorder characterized by ataxia and cerebellar atrophy due to synaptic degeneration in the molecular layer and massive apoptosis of granule neurons. To investigate the molecular triggers of neurological dysfunction, we have carried out differential proteomic analysis of cerebellar tissue from Tg(PG14) mice at the preclinical, onset and symptomatic phases of their neurological illness. Two-dimensional maps of cerebellar proteins from Tg(PG14) mice were compared to those obtained from age-matched Tg(WT) mice that express wild-type PrP and remain healthy. We found 24 proteins whose levels were significantly modified in at least one stage of the Tg(PG14) disease. These proteins were identified by peptide mass fingerprinting using MALDI mass spectrometry, and their variations were confirmed by Western blot analysis. The identified proteins include calcium-binding proteins, proteins involved in cellular metabolism, oxidative stress, and structural proteins. Interestingly, our analysis revealed that the level of the calcium/calmodulin-dependent phosphatase calcineurin was reduced by 50% starting from the presymptomatic stage, due to downregulation of the enzyme in cerebellar granule neurons. These results indicate that dysregulation of calcium-dependent phosphatase activity may represent a primary pathogenic event triggered by PG14 PrP.
AD Emiliano Biasini, Valentina Rossi, Tania Massignan, Luana Fioriti, Sara Dossena, Valentina Bonetto, Roberto Chiesa, Dulbecco Telethon Institute, Milan, Italy; Emiliano Biasini, Valentina Rossi, Tania Massignan, Luana Fioriti, Sara Dossena, Mario Salmona, Gianluigi Forloni, Valentina Bonetto, Roberto Chiesa, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
SP englisch
PO Deutschland