Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease

Roberto Chiesa, Pedro Piccardo, Sara Dossena, Lisa Nowoslawski, Kevin A Roth, Bernardino Ghetti, David A Harris

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)238-43
Number of pages6
JournalProceedings of the National Academy of Sciences
Issue number1
Publication statusPublished - 4 Jan 2005


  • Animals
  • Apoptosis
  • Cerebellum
  • Disease Models, Animal
  • Gene Deletion
  • Mice
  • Mice, Transgenic
  • Neurons
  • Prion Diseases
  • Prions
  • Proto-Oncogene Proteins c-bcl-2
  • Synapses
  • bcl-2-Associated X Protein


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