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 tran sgene coding for normal DM-20, the alternatively spliced quantitativel y minor isoform of myelin proteolipid protein. Demyelination of the CN S occurs as a consequence of 70 copies of this transgene. Overt sympto ms begin at similar to 3 months with a wobbling gait. Occasional seizu res 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-m onth-old animals, before the onset of any overt symptoms, appears morp hologically normal at the electron microscopic level. However, the mye lin in these 2-month-old animals has a reduced amount of the major mye lin proteolipid protein and about three times as much DM-20 as normal animals. in 7-month-old animals that appear to be undergoing demyelina tion in the CNS, both the major myelin proteolipid protein and DM-20 a re greatly reduced relative to the 2-month-old animal. Mice with 17 co pies of the transgene also have a reduced amount of the major myelin p roteolipid protein but appear to be otherwise normal and have normal l ife spans (>2 yr). Mice with low copy numbers of the transgene (2-4 co pies) appear to be unaffected and have normal life spans.