Transgenic and natural mouse models of proteolipid protein (PLP)-related dysmyelination and demyelination.

The X chromosome-linked PLP/DM-20 gene is the CNS myelin gene most frequently associated with mutations, resulting in dysmyelination in several species including man (Pelizaeus-Merzbacher disease, X-linked Spastic Paraplegia). The pathology of most PLP gene mutations is characterized by hypomyelination, glial cell proliferation, increased numbers of microglia, and premature oligodendrocyte death. In most mutants, residual myelin structures have an abnormal ultrastructure and periodicity. Surprisingly, transgenic mice which carry extra copies of the wild type PLP gene show dysmyelination, demonstrating that the PLP gene is dosage sensitive. Pathological changes of transgenic mice vary from the phenotype of natural mutants. Specifically, many Golgi saccules of oligodendrocytes are vacuolated and the cytoplasm contains autophagic vacuoles hinting at a perturbation in protein trafficking. In fact, upon transgenic overexpression PLP becomes a prominent peripheral myelin protein, whereas in normal Schwann cells PLP is restricted from entering the myelin compartment. Surprisingly, transgenic animals which overexpress PLP/DM-20 at a low level appear normal during early development, but later spontaneously demyelinate. The mechanisms underlying this demyelination phenotype is unknown but an immune-mediated process has been suggested. All attempts to correct the phenotype of natural PLP mutants, such as jimpy mice, with a wild type transgene have had little effects, indicating a dominant-negative effect of the mutant gene product. On the other hand, mice with a targeted disruption of the PLP/DM-20 gene have surprisingly minor clinical signs. This suggests that the lethal phenotype associated with the majority of PLP gene mutations is a complex combination of loss and gain-of-function effects of a mutant myelin protein.