BRAIN GLYCOLIPIDS: METABOLISM AND PATHOLOGY

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The group of proteins which activate three sphingolipid hydrolases (glucocerebrosidase, galatocerebrosidase, and sphingomyelinase) will be studied in depth. We will develop an immunoassay for measuring their concentration in different brain cell types and subcellular fractions, organs, and fluids. Changes in these concentrations as a function of age and physiological state, including genetic disorders of sphingolipid metabolism, will be measured in an effort to elucidate their functions. The antibodies will also be used to prepare and immunoaffinity column as an aid in the large-scale isolationof the activators. Chemical studies will be made with the activaters to determine their amino acid sequences and to identify the regions needed for activating the enzymes. It may be possible to use the activators as stabilizers of the enzymes in order to improve the effeciveness of enzyme therapy of the disorders (especially Gaucher disease). Similar studies will be made of the proteins which aid in the transfer of cerebrosides between membranes. We will try to prepare active degradation products of the proteins and also see if the proteins stimulate the action of various glycopid synthetases. Further study of the changes in brain sphingolipids that are produced by fasting will be done. We will investigate the possibility that the level of free fatty acids in brain controls the level of ceramide. Enzyme studies will be carried out in brain membrane fractions to see if there are indeed five enzymes for synthesizing ceramide. Identification of the pathway for sphingomyelin synthesis in brain will be attempted. The value of a new video densitometer in lipid analysis will be determined.