Biochemical analysis of myelin lipids and proteins in a model of methyl donor pathway deficit: Effect of S-adenosylmethionine

S-Adenosylmethionine (SAMe) is the methyl donor to numerous acceptor molecu les. We used cyclo-leucine (CL), which prevents the conversion of methionin e to SAMe by inhibiting ATP-L-methionine-adenosyltransferase (MAT), to char acterize the lipid and protein changes induced in peripheral nerve and brai n myelin in rats during development. We also investigated the effect of exo genous SAMe by administering SAMe-1, 4-butane disulfonate (SAMe-SD4). CL wa s given on days 7, 8, 12, and 13 and SAMe-SD4 was given daily from day 7; t he animals were killed on day 18. CL accumulates in the brain reaching a co ncentration within 24 h compatible with its ID50 in vitro and interacting w ith methionine metabolism; brain MAT activity and SAMe levels were lower an d methionine levels higher than in controls. CL significantly reduced brain and nerve weight gains, brain myelin content, proteins, phospholipids, and galactolipids. Among phospholipids in nerve and brain, only sphingomyelin was significantly increased, by 35-50%. Sciatic nerve protein analyses show ed some significant changes: protein zero in sciatic nerve remained unchang ed but the 14.0- and 18.5-kDa isoforms of myelin basic protein showed a dra matic increase. Among the main proteins, in purified brain myelin, the prot eolipid protein and dimer-20 isoform decreased after CL. SAMe-SD4 highlight s some sensitive parameters by counteracting, at least partially, some alte rations of PL-particularly galactolipids and sphingomyelins-and proteins in duced by CL. The partial beneficial effects might also be explained by the age-related Limited bioavailability of exogenous SAMe, a finding, to our kn owledge, not yet reported elsewhere. This study demonstrates that availabil ity of methyl donors is closely related to the formation of myelin componen ts. (C) 1999 Academic Press.