3-DEAZAADENOSINE - A THERAPEUTIC STRATEGY FOR MYASTHENIA-GRAVIS BY DECREASING THE ENDOCYTOSIS OF ACETYLCHOLINE-RECEPTORS

The basic abnormality in myasthenia gravis is the depletion of acetylc holine receptors (AChRs) at neuromuscular junctions, which is due in p art to excessive endocytosis brought about by the action of pathogenic antibodies. We asked whether 3-deazaadenosine (3DZA), an inhibitor of phospholipid methylation, could decrease the rate of endocytosis of m uscle AChRs and thereby interfere with this pathological process. The rationale for the use of 3DZA is that methylation of phospholipids alt ers membrane properties, and inhibition of methyltransferase reactions is known to slow the process of endocytosis. In this study, we have t ested the effects of 3DZA and other methylation inhibitors on the degr adation and synthesis of AChRs in an in vitro model of myasthenia grav is, using primary rat skeletal muscle cultures and serum from human my asthenic patients. In normal cultures (without myasthenic serum), 3DZA inhibited AChR degradation with a broad dose-response relationship, b eginning as low as 2 muM (P < .0001). There was no acute effect on syn thesis of AChRs or on other measures of muscle cell integrity. When hu man myasthenic serum was added to the cultures to accelerate the endoc ytosis and degradation of AChRs, 3DZA still potently inhibited the deg radation rate. Because the drug allows accumulation of AChRs in the su rface membrane of the muscle cell by reducing endocytotic degradation, it provides a potential strategy for therapy in human myasthenia grav is.