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Concentrations of an Activator Protein for Sphingolipid Hydrolysis in Liver and Brain Samples from Patients with Lysosomal Storage Diseases

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Concentrations of an Activator Protein for Sphingolipid Hydrolysis in Liver and Brain Samples from Patients with Lysosomal Storage Diseases Concentrations of an activator protein for sphingolipid hydrolysis in liver and brain samples from patients with lysosomal storage diseases. K Inui, D A Wenger J Clin Invest. 1983;72(5):1622-1628. https://doi.org/10.1172/JCI111121. Research Article The hydrolysis of sphingolipids by lysosomal enzymes requires the presence of additional proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage process all remain to be determined. In this study, antibodies to an activator protein known to bind sphingolipids and activate the enzymatic hydrolysis of GM1 ganglioside and sulfatide were used to estimate the concentration of this activator protein in small samples of liver and brain from patients with lysosomal storage diseases. By using rocket immunoelectrophoresis, the concentration of cross-reacting material (CRM) was determined. Control livers had an average of 0.95 +/- 0.18 (mean +/- 1 SD) microgram CRM/mg protein in the extracts, and control brains had an average of 0.25 +/- 0.14 microgram CRM/mg protein. Extremely high levels of CRM were found in extracts of livers from patients with type 1 GM1 gangliosidosis (15.1 and 16.9), and type A Niemann-Pick disease (10.7). Extracts of brain samples revealed a large amount of CRM in type 1 GM1 gangliosidosis (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff disease (13.5). Significantly elevated CRM was also measured in brain samples from patients with type 2 GM1 gangliosidosis, type A Niemann-Pick disease, metachromatic leukodystrophy, and Krabbe disease. The highest levels are found in those genetic diseases where the lipids stored, […] Find the latest version: https://jci.me/111121/pdf Concentrations of an Activator Protein for Sphingolipid Hydrolysis in Liver and Brain Samples from Patients with Lysosomal Storage Diseases KojI INUI and DAVID A. WENGER, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado 80262 A B S T R A C T The hydrolysis of sphingolipids by ly- the cause of clinical, biochemical, and pathological sosomal enzymes requires the presence of additional heterogeneity found in the patients. proteins, which have been called activator proteins. The number of activator proteins, their specificity, exact mechanism of action, and response to a storage INTRODUCTION process all remain to be determined. In this study, Sphingolipids are degraded in the lysosomes by the antibodies to an activator protein known to bind sphin- sequential action of specific acid hydrolases. A mu- golipids and activate the enzymatic hydrolysis of GM, tation in one of these enzymes can result in a lack of ganglioside and sulfatide were used to estimate the sufficient activity to prevent accumulation of one or concentration of this activator protein in small samples more substrates, and this can lead to severe clinical of liver and brain from patients with lysosomal storage deterioration in a patient. The activity of these lipid diseases. By using rocket immunoelectrophoresis, the hydrolases can be measured in vitro using either a syn- concentration of cross-reacting material (CRM) was thetic substrate or a suitably labeled natural substrate determined. Control livers had an average of 0.95±0.18 usually assayed in the presence of a specific detergent. (mean±1 SD) ,ug CRM/mg protein in the extracts, and Recently, it has become evident that mammalian tis- control brains had an average of 0.25±0.14 ,Ag CRM/ sues contain proteins that act either as natural acti- mg protein. Extremely high levels of CRM were found vators by binding the lipid substrates and carrying in extracts of livers from patients with type 1 GM1 them to the specific hydrolase or as a cofactor by bind- gangliosidosis (15.1 and 16.9), and type A Niemann- ing to the hydrolase to prepare it for the substrate. Pick disease (10.7). Extracts of brain samples revealed These include the activators of sulfatide sulfatase (1, a large amount of CRM in type 1 GM1 gangliosidosis 2), glucosylceramide ,B-glucosidase (3), GM1 ganglioside (14.8), Tay-Sachs disease (5.3 and 8.7), and Sandhoff B-galactosidase (4, 5), GM2 ganglioside ,B-hexosamini- disease (13.5). Significantly elevated CRM was also dase A (6, 7), sphingomyelinase (8, 9), and galacto- measured in brain samples from patients with type 2 sylceramide f3-galactosidase (10). The exact number GM1 gangliosidosis, type A Niemann-Pick disease, of activator proteins is not known, and some activator metachromatic leukodystrophy, and Krabbe disease. proteins with different specificities appear to be iden- The highest levels are found in those genetic diseases tical. For example, recent studies in this laboratory where the lipids stored, primarily or secondarily to the (10) demonstrated that the activator protein for glu- genetic defect, bind to this activator protein. This ac- cosylceramide f-glucosidase (3) may be identical to tivator protein may have an important function in reg- the activator of galactosylceramide ,8-galactosidase. ulating intralysosomal lipid catabolism, and changes Recently, the activator protein originally reported to in its concentration in certain genetic diseases may be activate GM1 ganglioside f-galactosidase (5) was found to be missing in cultured cells from a patient who was unable to properly metabolize sulfatide (11). This pro- Address reprint requests to Dr. Wenger. vides evidence that the activator of GM, ganglioside Received for publication 31 March 1983 and in revised may be identical to the activator of sulfatide sulfatase form 7 June 1983. originally described by Mehl and Jatzkewitz (1). This 1622 J. Clin. Invest. ©) The American Society for Clinical Investigation, Inc. * 0021-9738/83/11/1622/07 $1.00 Volume 72 Novemnber 1983 1622-1628 activator's exact mechanism of action and response to enzymes to act on their substrates and this could result a defect in lysosomal function is not known. in clinical heterogeneity among patients with the same The role that activator proteins play in the etiology enzymatic defect. of certain genetic lipidoses has only recently been elucidated. Conzelmann and Sandhoff (7) and Hecht- METHODS man et al. (12) have described patients who store GM2 Purification of the activator protein. The activator pro- ganglioside because of a deficiency of the activator tein, originally demonstrated to stimulate the enzymic hy- drolysis of GM, ganglioside by ,B-galactosidase, was purified protein toward GM2 ganglioside f,-hexosaminidase A. from liver samples from a control and a patient who died Li et al. (13) and our laboratory (14) reported that with type 1 GM, gangliosidosis by using the method of Li other patients who store GM2 ganglioside had normal and Li (5). The purification was described in our previous (or elevated) levels of this activator protein and ap- communication (17). Although the liver from the patient had about 35 times more of the activator protein than the control parently normal ,3-hexosaminidase A levels (using syn- used, both had identical properties with regard to lipid bind- thetic substrates for assay). The defect in these patients ing, ability to stimulate only specific enzymatic reactions, appears to be in the activator protein or lipid-binding and both gave only one diffuse band with Coomassie Blue site on their f3-hexosaminidase A. Christomanou (8) staining on polyacrylamide gel electrophoresis in the pres- reported a defect in a sphingomyelinase activator pro- ence and absence of sodium dodecyl sulfate (11, 17).2 From 200-g samples of liver, 0.65 mg and 24 mg of activator pro- tein in some patients with juvenile Niemann-Pick dis- tein were isolated from the control and the patient, respec- ease, but this has not been confirmed. Shapiro et al. tively. (15) reported on patients with a juvenile form of meta- Preparation of immune serum to this activator protein. chromatic leukodystrophy who had only partially de- Each of two young female rabbits was injected with 10 yg A of purified activator protein from GMI gangliosidosis liver ficient arylsulfatase activity. Recently, our labora- emulsified in Freund's incomplete adjuvent into each shoulder tory (11) demonstrated correction of in situ sulfatide region as recently described (15). After 2½/2 wk another 20 metabolism in the skin fibroblasts from one of these ,ug per rabbit was injected into the haunches in the same patients by the addition of the activator protein orig- manner. 4 wk after the initial injection, precipitin lines were inally demonstrated to stimulate ganglioside detected by Ouchterlony double immunodiffusion in 1.2% GM, agarose gels. The rabbits were boosted by injecting 20 ug f,-galactosidase (5). In addition, by using monospecific activator protein followed by collection of blood from an ear antiserum to this activator protein, the patient's cul- artery 1 wk later. Sera were prepared and frozen in aliquots tured cells were found to contain no cross-reacting after addition of 1/100 part of 1 M e-aminocaproic acid. No material (CRM)' (11). precipitin lines were detected with the preimmune rabbit It is sera. The crude IgG fraction was prepared by the addition known that the activator protein that stimulates of an equal volume of saturated ammonium sulfate to the the enzymatic hydrolysis of GM, ganglioside and sul- serum and collection of the precipitate. fatide acts by binding the lipid substrates and pre- The specificity of the antiserum toward this protein was senting them to their specific lysosomal hydrolase determined by several criteria. Ouchterlony double immu- (16).2 However, it can also bind other sphingolipids nodiffusion using the crude antiserum gave only one precip- itin line with crude extracts of liver and brain. Two precip- but not stimulate their hydrolysis when presented with itin lines were obtained when the crude IgG fraction was the specific lysosomal hydrolase.2 Because of this find- used with pure activator protein and crude tissue extracts.
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