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 journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)238-243
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number1
DOIs
StatePublished - Jan 4 2005

Keywords

  • Apoptosis
  • Cerebellum
  • Neurodegeneration
  • Synapse

ASJC Scopus subject areas

  • Genetics
  • General

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