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 peripheral and central nervous myelin were produced by microinjecting murine genomic 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 postnatal 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) has profound consequences for myelin formation and maintenance: approximately twofold overexpression of PLP/DM-20, as seen in homozygotes, results in apoptosis of mature, and a developmental arrest of the remaining immature oligodendrocytes. Severe dysmyelination ensues, associated with reactive astrogliosis and microglia activation/proliferation. Activation of microglia is also prominent in hemizygous rats with low levels of transgene overexpression. In these animals, myelin sheaths remain intact, but there is low-grade myelin degeneration throughout life witnessed by myelin uptake and activation of microglia and astrocytes, in the absence of the expression of major histocompatibility complex class II gene products. There were no spontaneous lymphocytic infiltrates in areas of myelin degeneration. However, hemizygous LEW.PLP rats were more sensitive to experimental autoimmune encephalomyelitis mediated by T cells specific for PLP, but not another encephalitogenic myelin protein, MBP.
Bradl
M
M
Max-Planck-Institut für Neurobiologie, Martinsried, Germany.
Bauer
J
J
Inomata
T
T
Zielasek
J
J
Nave
K A
KA
Toyka
K
K
Lassmann
H
H
Wekerle
H
H
D000818:Animals; D001327:Autoimmune Diseases / Q000473:pathology*; D004679:Encephalomyelitis / Q000473:pathology*; D008854:Microscopy, Electron; D018991:Myelin Proteolipid Protein / Q000032:analysis*; D009186:Myelin Sheath / Q000473:pathology* / Q000648:ultrastructure; D009410:Nerve Degeneration / Q000473:pathology* / Q000503:physiopathology; D009431:Neural Conduction / Q000502:physiology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000473:pathology
D018991:Myelin Proteolipid Protein; D012333:RNA, Messenger