MECHANISM OF DEMYELINATION IN DM20 TRANSGENIC MICE INVOLVES INCREASEDFATTY ACYLATION

Transgenic mice (ND4) containing 70 copies of the transgene encoding D M20 were clinically normal up to 3 months of age, spontaneously demyel inated thereafter and died in 8-10 months. Whereas the myelin fraction from normal mice increased in amount from 1-4 months as expected, the corresponding fraction in ND4 mice remained constant over this period . In order to study the mechanism by which decreased myelin synthesis was manifest in the ND4 mouse, we investigated the amounts of proteoli pids at various ages. The amount of proteolipid protein (PLP) was grea tly decreased after 1-2 months in the ND4 mice. Although the message f or DM20 was increased (transgene mRNA), very little DM20 was found in myelin at 1 month. It subsequently increased so that at 3-4 months the amount of DM20 in myelin isolated from transgenic animals was much hi gher than in normal mice. Characterization of the DM20 and PLP at 1 mo nth of age showed that the amount of fatty acid (stearate and palmitat e) was increased and the N-terminal glycine was methylated. These data suggested that high copy numbers of the cDNA for DM20 affected post t ranslational events which we postulate affected the proper insertion o f both DM20 and PLP in the myelin bilayer. J. Neurosci. Res. 53:143-15 2, 1998. (C) 1998 Wiley-Liss, Inc.