NR AVZQ
AU Baumann,F.; Tolnay,M.; Brabeck,C.; Pahnke,J.; Kloz,U.; Niemann,H.H.; Heikenwalder,M.; Rülicke,T.; Bürkle,A.; Aguzzi,A.
TI Lethal recessive myelin toxicity of prion protein lacking its central domain
QU EMBO Journal 2007 Jan 24; 26(2): 538-47
PT journal article; research support, non-u.s. gov't
AB PrPc-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP(DeltaF)) suffer from neurodegeneration, which is rescued by full-length PrPc. We now report that expression of PrP(DeltaCD), a PrP variant lacking 40 central residues (94-134), induces a rapidly progressive, lethal phenotype with extensive central and peripheral myelin degeneration. This phenotype was rescued dose-dependently by coexpression of full-length PrPc or PrPc lacking all octarepeats. Expression of a PrPc variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrPc, yet enhanced the toxicity of PrP(DeltaCD) and diminished that of PrP(DeltaF). Therefore, deletion of the entire central domain generates a strong recessive-negative mutant of PrPc, whereas removal of residues 114-121 creates a partial agonist with context-dependent action. These findings suggest that myelin integrity is maintained by a constitutively active neurotrophic protein complex involving PrPc, whose effector domain encompasses residues 94-134.
MH Animals; Gene Deletion; Genes, Lethal; Genes, Recessive; Mice; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Models, Biological; Mutant Proteins/physiology; Myelin Sheath/*metabolism; PrPc Proteins/chemistry/*genetics/physiology; Protein Structure, Tertiary; Survival Analysis
AD Institute of Neuropathology, University Hospital of Zürich, Zürich, Switzerland.
SP englisch
PO England