Over-expression of the DM-20 myelin proteolipid causes central nervous system demyelination in transgenic mice.
We have created transgenic mice bearing varying copy numbers of a transgene coding for normal DM-20, the alternatively spliced quantitatively minor isoform of myelin proteolipid protein. Demyelination of the CNS occurs as a consequence of 70 copies of this transgene. Overt symptoms begin at approximately 3 months with a wobbling gait. Occasional seizures lasting a few seconds begin at 3-4 months. These symptoms progress in severity with age. Death occurs by 8-10 months. Myelination in 2-month-old animals, before the onset of any overt symptoms, appears morphologically normal at the electron microscopic level. However, the myelin in these 2-month-old animals has a reduced amount of the major myelin proteolipid protein and about three times as much DM-20 as normal animals. In 7-month-old animals that appear to be undergoing demyelination in the CNS, both the major myelin proteolipid protein and DM-20 are greatly reduced relative to the 2-month-old animal. Mice with 17 copies of the transgene also have a reduced amount of the major myelin proteolipid protein but appear to be otherwise normal and have normal life spans (> 2 yr). Mice with low copy numbers of the transgene (2-4 copies) appear to be unaffected and have normal life spans.
Johnson
R S
RS
Department of Biochemistry, University of Toronto, Hospital for Sick Children, Ontario, Canada.
Roder
J C
JC
Riordan
J R
JR
D017398:Alternative Splicing; D000818:Animals; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009185:Myelin Proteins / Q000235:genetics*; D018991:Myelin Proteolipid Protein; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger / Q000235:genetics; D014158:Transcription, Genetic
D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D009419:Nerve Tissue Proteins; C047516:Plp1 protein, mouse; D012333:RNA, Messenger