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

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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
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

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Prion Diseases
Phenotype
bcl-2 Genes
Nerve Degeneration
Cerebellar Ataxia
Synaptophysin
Mutant Proteins
Nervous System Diseases
Cerebellum
Nervous System
Atrophy
Cell Death
Apoptosis
Neurons

Keywords

  • Apoptosis
  • Cerebellum
  • Neurodegeneration
  • Synapse

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease. / Chiesa, Roberto; Piccardo, Pedro; Dossena, Sara; Nowoslawski, Lisa; Roth, Kevin A.; Ghetti, Bernardino; Harris, David A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 102, No. 1, 04.01.2005, p. 238-243.

Research output: Contribution to journalArticle

Chiesa, Roberto ; Piccardo, Pedro ; Dossena, Sara ; Nowoslawski, Lisa ; Roth, Kevin A. ; Ghetti, Bernardino ; Harris, David A. / Bax deletion prevents neuronal loss but not neurological symptoms in a transgenic model of inherited prion disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2005 ; Vol. 102, No. 1. pp. 238-243.
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