NR ARON
AU Chiesa,R.; Piccardo,P.; Dossena,S.; Nowoslawski,L.; Roth,K.A.; Ghetti,B.; Harris,D.A.
TI Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease
QU Proceedings of the National Academy of Sciences of the United States of America 2005 Jan 4; 102(1): 238-43
IA http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=544044
PT journal article
AB 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.
MH Animals; Apoptosis/physiology; Cerebellum/metabolism; Disease Models, Animal; *Gene Deletion; Mice; Mice, Transgenic; Neurons/*metabolism; Prion Diseases/*genetics/metabolism/physiopathology; Prions/*metabolism; Proto-Oncogene Proteins c-bcl-2/*genetics/metabolism; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.; Synapses/metabolism
AD Dulbecco Telethon Institute and Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri, 20157 Milan, Italy. chiesa@marionegri.it
SP englisch
PO USA