title: Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease.
abstract: Transgenic Tg(PG14) mice express a mutant prion protein containing 14 octapeptide repeats, whose human homologue is associated with an inherited prion dementia. These mice develop a progressive neurological disorder characterized by ataxia and cerebellar atrophy, with massive apoptotic degeneration of granule neurons. Bax, a proapoptotic gene of the Bcl-2 family, plays a key role in regulating cell death in the nervous system. To analyze the role of Bax in the Tg(PG14) phenotype, we crossed Tg(PG14) mice with Bax(-/-) mice to obtain Tg(PG14)/Bax(-/-) offspring. Bax deletion effectively rescued cerebellar granule neurons from apoptosis, implying that these cells die via a Bax-dependent process. Surprisingly, however, the age at which symptoms began and the duration of the clinical phase of the illness were not altered in Tg(PG14)/Bax(-/-) mice. In addition, Bax deletion failed to prevent shrinkage of the molecular layer of the cerebellum and loss of synaptophysin-positive synaptic endings. Our analysis indicates that synaptic loss makes a critical contribution to the Tg(PG14) phenotype. These results provide insights into the pathogenesis of prion diseases and have important implications for the treatment of these disorders.
authors.affiliation: Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy. chiesa@marionegri.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Chiesa
authors.forename: Pedro
authors.initials: P
authors.lastname: Piccardo
authors.forename: Sara
authors.initials: S
authors.lastname: Dossena
authors.forename: Lisa
authors.initials: L
authors.lastname: Nowoslawski
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Roth
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: David A
authors.initials: DA
authors.lastname: Harris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D017096:Prion Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011328:Prions / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: C494827:Bax protein, mouse; D011328:Prions; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein