GLIAL-CELL DEGENERATION AND HYPOMYELINATION CAUSED BY OVEREXPRESSION OF MYELIN PROTEOLIPID PROTEIN GENE

Myelin proteolipid protein (PLP), the major myelin protein in the CNS, has been thought to function in myelin assembly. Thus, mutations with in the gene coding for PLP (Plp) cause hypomyelination, such as the ji mpy phenotype in mice and Pelizaeus-Merzbacher disease in humans. Howe ver, these mutants often exhibit premature death of oligodendrocytes, which form CNS myelin. To elucidate the functional roles of Plp gene p roducts in the maturation and/or survival of oligodendrocytes, we prod uced transgenic mice overexpressing the Plp gene by introducing extra wild-type mouse Plp genes. Surprisingly, transgenic mice bearing 4 mor e Plp genes exhibited dysmyelination in the CNS, whereas those with 2 more Plp genes showed normal myelination at an early age (3 weeks afte r birth), but later developed demyelination. Overexpression of the Plp gene resulted in arrested maturation of oligodendrocytes, and the sev erity of arrest was dependent on the extent of overexpression. Overexp ression also led to oligodendrocyte cell death, apparently caused by a bnormal swelling of the Golgi apparatus. Thus, tight regulation of Plp gene expression is necessary for normal oligodendrocyte differentiati on and survival, and its overexpression can be the cause of both dys- and demyelination.