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

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...

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Bibliographic Details
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
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0406173102