Transgenic Lewis rats overexpressing the proteolipid protein gene: myelin degeneration and its effect on T cell-mediated experimental autoimmune encephalomyelitis

Transgenic Lewis rats overexpressing proteolipid protein (PLP) genes in per ipheral and central nervous myelin were produced by microinjecting murine g enomic PLP sequences into fertilized eggs. The mouse PLP gene shares 98.7% homology in the nucleotide sequence with its rat counterpart, but both are fully identical on protein level. Homozygous rats show tremors early in pos tnatal life, eventually develop seizures, and die before they reach weaning age, while hemizygous animals are phenotypically normal and have a normal life expectancy. Transgene expression in the central nervous system (CNS) h as profound consequences for myelin formation and maintenance: approximatel y twofold overexpression of PLP/DM-20, as seen in homozygotes, results in a poptosis of mature, and a developmental arrest of the remaining immature ol igodendrocytes. Severe dysmyelination ensues, associated with reactive astr ogliosis and microglia activation/proliferation. Activation of microglia is also prominent in hemizygous rats with low levels of transgene overexpress ion. In these animals, myelin sheaths remain intact, but there is low-grade myelin degeneration throughout life witnessed by myelin uptake and activat ion of microglia and astrocytes, in the absence of the expression of major histocompatibility complex class II gene products. There were no spontaneou s lymphocytic infiltrates in areas of myelin degeneration. However, hemizyg ous LEW.PLP rats were more sensitive to experimental autoimmune encephalomy elitis mediated by T cells specific for PLP, but not another encephalitogen ic myelin protein, MBP.