Bax Deletion Prevents Neuronal Loss but Not Neurological Symptoms in a Transgenic Model of Inherited Prion Disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-01, Vol.102 (1), p.238-243
• Main Authors: Chiesa, Roberto, Piccardo, Pedro, Dossena, Sara, Nowoslawski, Lisa, Roth, Kevin A., Ghetti, Bernardino, Harris, David A., Wickner, Reed B.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - physiology; bcl-2-Associated X Protein; Biological Sciences; Cell death; Cerebellum; Cerebellum - metabolism; Disease Models, Animal; Gene Deletion; Genes; Genotypes; Mice; Mice, Transgenic; Mutation; Neurological disorders; Neurology; Neurons; Neurons - metabolism; Neuroscience; Pathology; Peptides; Prion diseases; Prion Diseases - genetics; Prion Diseases - metabolism; Prion Diseases - physiopathology; Prions - metabolism; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Rodents; Synapses; Synapses - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0406173102

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.