Disruption of Doppel Prevents Neurodegeneration in Mice with Extensive Prnp Deletions

The Prnp gene encodes the cellular prion protein PrPC. Removal of its ORF does not result in pathological phenotypes, but deletions extending into the upstream intron result in cerebellar degeneration, possibly because of ectopic cis-activation of the Prnd locus that encodes the PrPChomologue Doppel...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2004-03, Vol.101 (12), p.4198-4203
Main Authors: Genoud, Nicolas, Behrens, Axel, Miele, Gino, Robay, Dimitri, Heppner, Frank L., Freigang, Stefan, Aguzzi, Adriano, Weissmann, Charles
Format: Article
Language:English
Subjects:
Alleles
Amyloid - genetics
Amyloid - metabolism
Animals
Biological Sciences
Cerebellar Ataxia - genetics
Cerebellar Ataxia - metabolism
Cerebellar Ataxia - pathology
Cerebellum - pathology
Comparative analysis
Gene expression
Genetic loci
GPI-Linked Proteins
Immune System - immunology
Infertility, Male - genetics
Infertility, Male - metabolism
Male
Male animals
Mice
Neurodegenerative Diseases - genetics
Neurodegenerative Diseases - metabolism
Neurology
Phenotypes
Prion Proteins
Prions
Prions - genetics
Prions - metabolism
Protein Precursors - genetics
Protein Precursors - metabolism
Rodents
Sequence Deletion
Spermatozoa
Spleen
T lymphocytes
Testes
Time Factors
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Summary:The Prnp gene encodes the cellular prion protein PrPC. Removal of its ORF does not result in pathological phenotypes, but deletions extending into the upstream intron result in cerebellar degeneration, possibly because of ectopic cis-activation of the Prnd locus that encodes the PrPChomologue Doppel (Dpl). To test this hypothesis, we removed Prnd from Prnpo/ omice by transallelic meiotic recombination. Balanced loxP-mediated ablation yielded mice lacking both PrPCand Dpl (Prno/ o), which developed normally and showed unimpaired immune functions but suffered from male infertility. However, removal of the Prnd locus abolished cerebellar degeneration, proving that this phenotype is caused by Dpl upregulation. The absence of compound pathological phenotypes in Prno/ omice suggests the existence of alternative compensatory mechanisms. Alternatively, Dpl and PrPCmay exert distinct functions despite having partly overlapping expression profiles.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0400131101