Lethal recessive myelin toxicity of prion protein lacking its central domain

PrP^C-deficient mice expressing prion protein variants with large amino-proximal deletions (termed PrP_ΔF) suffer from neurodegeneration, which is rescued by full-length PrP^C. We now report that expression of PrP_ΔCD, 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 _ΔCD and diminished that of PrP_ΔF. 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.