PrP(C)-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP(DeltaF)) suffer from neurodegeneration, which is rescued by full-length PrP(C). 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 PrP(C) or PrP(C) lacking all octarepeats. Expression of a PrP(C) variant lacking eight residues (114-121) was innocuous in the presence or absence of full-length PrP(C), 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 PrP(C), 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 PrP(C), whose effector domain encompasses residues 94-134.