Lethal recessive myelin toxicity of prion protein lacking its central domain

Abstract

PrPC‐deficient mice expressing prion protein variants with large amino‐proximal deletions (termed PrPΔF) suffer from neurodegeneration, which is rescued by full‐length PrPC. We now report that expression of PrPΔCD, 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 PrPΔCD and diminished that of PrPΔF. 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.