NR AQJO
AU Genoud,N.; Behrens,A.; Miele,G.; Robay,D.; Heppner,F.L.; Freigang,S.; Aguzzi,A.
TI Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions
QU Proceedings of the National Academy of Sciences of the United States of America 2004 Mar 23; 101(12): 4198-203
PT journal article
AB 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 PrPc homologue Doppel (Dpl). To test this hypothesis, we removed Prnd from Prnp(o/o) mice by transallelic meiotic recombination. Balanced loxP-mediated ablation yielded mice lacking both PrPc and Dpl (Prn(o/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 Prn(o/o) mice suggests the existence of alternative compensatory mechanisms. Alternatively, Dpl and PrPc may exert distinct functions despite having partly overlapping expression profiles.
MH Amyloid/*genetics/metabolism; Animals; Cerebellar Ataxia/genetics/metabolism/pathology; Cerebellum/pathology; Immune System/immunology; Infertility, Male/genetics/metabolism; Male; Mice; Neurodegenerative Diseases/*genetics/metabolism; Prions/*genetics/metabolism; Protein Precursors/*genetics/metabolism; Sequence Deletion; Support, Non-U.S. Gov't; Time Factors
AD Institute of Neuropathology, University Hospital Zürich, Schmelzbergstrasse 12, CH-8091 Zürich, Switzerland.
SP englisch
PO USA