DOMINANT-NEGATIVE ACTION OF THE JIMPY MUTATION IN MICE COMPLEMENTED WITH AN AUTOSOMAL TRANSGENE FOR MYELIN PROTEOLIPID PROTEIN

Mutations in genes encoding membrane proteins have been associated wit h cell death of unknown cause from invertebrate development to human d egenerative diseases. A point mutation in the gene for myelin proteoli pid protein (PLP) underlies oligodendrocyte death and dysmyelination i n jimpy mice, an accurate model for Pelizaeus-Merzbacher disease. To d istinguish the loss of PLP function from other effects of the misfolde d protein, we took advantage of the X chromosomal linkage of the gene and have complemented jimpy with a wild-type PLP transgene, In this ar tificial heterozygous situation, the jimpy mutation emerged as genetic ally dominant. At the Cellular level oligodendrocytes showed little in crease in survival although endogenous PLP gene and autosomal transgen e were truly coexpressed. In surviving oligodendrocytes, wild-type PLP was functional and immunodetectable in myelin. Moreover, compacted my elin sheaths regained their normal periodicity. This strongly suggests that, despite the presence of functional wild-type PLP, misfolded jim py PLP is by itself the primary cause of abnormal oligodendrocyte deat h.