Abstract
Neurological dysfunction and structural cerebral abnormalities are commonly found in patients with methylmalonic and propionic acidemia. However, the mechanisms underlying the neuropathology of these disorders are poorly understood. We have previously demonstrated that methylmalonic and propionic acids induce a significant reduction of ganglioside N-acetylneuraminic acid in the brain of rats subjected to chronic administration of these metabolites. In the present study, we investigated the in vivo effects of chronic administration of methylmalonic (MMA) and propionic (PA) acids (from the 6th to the 28th day of life) on the distribution and composition of gangliosides in the cerebellum and cerebral cortex of rats. Control rats were treated with the same volumes of saline. It was first verified that MMA and PA treatment did not modify body, cerebellum, or cortical weight, nor the ganglioside concentration in the cerebral cortex of the animals. In contrast, a significant reduction in total ganglioside content in the cerebellum of approximately 20–30% and 50% of control levels occurred in rats injected with MMA and PA, respectively. Moreover, chronic MMA and PA administration did not interfere with the ganglioside pattern in the cerebral cortex, whereas the distribution of individual gangliosides was altered in the cerebellum of MMA- and PA-treated animals. Rats injected with MMA demonstrated a marked decrease in GM1 and GD3, whereas chronic PA treatment provoked a significant reduction of all ganglioside species, with the exception of an increase in GM2. Since gangliosides are closely related to the dendritic surface and other neural membranes, indirectly reflecting synaptogenesis, these ganglioside abnormalities may be associated with the brain damage found in methylmalonic and propionic acidemias.
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REFERENCES
Ando, S. (1983). Gangliosides in the nervous system. Neurochem. Int. 5:507–537.
Bergman, A.I.W., van der Knapp, M.S., Smeitink, A.M., Duran, M., Dorland, L., Valk, J., and Poll, B.T. (1996). Magnetic resonance imaging and spectroscopy of brain in propionic acidemia: Clinical and biochemical consideration. Pediatr. Res. 40:404–409.
Brismar, J., and Ozand, P.T. (1994). MR of the brain in disorders of propionate and methylmalonate metabolism. Am. J. Neuroradiol. 15:1459–1473.
Brusque, A.M., Malfussi, H.F.C., Rocha, M.P., Dutra-Filho, C.S., Wanmacher, C.M.D., and Wajner, M. (1997). Propionic acid inhibits in vitro CO2 production in cerebellum and cerebral cortex of suckling rats. Med. Sci. Res. 25:347–349.
Brusque, A.M., Rotta, L., Pettenezzo, L.F., Junqueira, D., Schwarzbold, C., Wyse, A.T., Wannmacher, C.M.D., Dutra-Filho, C.S., and Wajner, M. Chronic postnatal administration of methylmalonic acid provokes a decrease of myelin content and ganglioside N-acetylneuraminic acid concentration in cerebrum of young rats. (2001). Braz. J. Biol. Res. 34:227–231.
Brusque, A.M., Terraciano, S.T., Fontella, F.U., Vargas, C., da Silva, C.G., Wyse, A.T., Trindade, V.M.T., Wannmacher, C.M.D., and Wajner,M. (1998). Chronic administration of propionic acid reduces ganglioside N-acetylneuraminic acid concentration in cerebellum of young rats. J. Neurol. Sci. 158:121–124.
De Souza, C., Piesowicz, A.T., Brett, E.M., and Leonard, J.V. (1989). Focal changes in the globi pallidi associated with neurological dysfunction in methylmalonic acidemia. Neuropediatrics 20:199–201.
Dutra, J.C., Dutra-Filho, C.S., Cardozo, S.E., Wannmacher, C.M.D., Sarkis, J.J., and Wajner,M. (1993). Inhibition of succinate dehydrogenase and beta-hydroxybutyrate dehydrogenase activities by methylmalonate in brain and liver of developing rats. J. Inher. Metab. Dis. 16:147–153.
Dutra, J.C., Wajner, M., Wannmacher, C.M.D., Wannmacher, L.E., Pires, R.F., and Rosa-Junior, A. (1991). Effect of postnatal methylmalonate administration on adult rat behavior. Braz. J. Med. Biol. Res. 24:595–605.
Farooqui, A.A., Liss, L., and Horrocks, L.A. (1988). Neurochemical aspects of Alzheimer's disease: Involvement of membrane phospholipids. Metab. Brain Dis. 3:19–35.
Fenton,W.A., Gravel, R.A., and Rosenblat, D.S. (2001). Disorders of proprionate and methylmalonate metabolism. In (C.R. Scriver, A.L. Beaudet, W.S. Sky, and D. Valle, eds.), The metabolic and Molecular Bases of Inherited Disease, 8th edn., McGraw-Hill, New York, pp. 2165–2194.
Ferrari, G., and Greene, L.A. (1998). Promotion of neuronal sruvival by GM1 ganglioside. Phenomenology and mechanisn of action. Ann NY Acad. Sci. 845:263–273.
Folch, J., Lees, M., and Sloane-Stanley, G.H. (1957). A simple method for the isolation and purification of total lipids from animal tissues. J. Biol. Chem. 226:497–509.
Fredman, P. (1998). Sphingolipids and cell signalling. J. Inherit. Metab. Dis. 21:472–480.
Gravel, R.A., Kaback, M.M., Proia, R.L., Sandhoff, K., Susuki, K., and Susuki, K. (2001). GM2 gangliosidoses. In (C.R. Scriver, A.L. Beaudet, W.S. Sky, and D. Valle, eds.), The Metabolic and Molecular Bases of Inherited Disease, 8th edn., McGraw-Hill, New York, pp. 3927–3876.
Hayasaka K., Metoki K., Satoh T., Nakisawa K., Tada K., Kawakami, T., Matsuo, N., and Aoki, T. (1982). Comparison of cytosolic and mitochondrial enzyme alterations in the liver of propionic or methylmalonic acidemia: Are reduction of cytochrome oxidase activity. Tohoku J. Exp. Med. 137:329–334.
Heidenreich, R., Natowicz, M., Hainline, B.E., Berman, P., Kelley, R.I., Hillman, R.E., and Berry, G.T. (1988). Acute extrapyramidal syndrome in methylmalonic acidemia: “Metabolic stroke” involving the globus pallidus. J. Pediatr. 113:1022–1027.
Hilbig, R., Rösner, H., and Rahman, H. (1981). Phylogenetic recapitulation of brain ganglioside composition during ontogenetic development. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 68:301–305.
Inokuchi, J., Kuroda,Y., Kosaka, S., and Fujiwara, M. (1998). L-Threo-1–phenyl-2–decanoylamino-3–morpholino-1–propanol stimulates ganglioside biosynthesis, neurite outgrowth and synapse formation in cultured cortical neurons, and ameliorates memory deficits in ischemic rats. Acta Biochim. Pol. 45:479–492.
Krahenbuhl, S., Chang, M., Bras, E.P., and Hoppel, C.L. (1991). Decreased activities of ubiquinol: ferricytochrome c oxidoredutase (Complex III) and ferrocytochrome c: oxygen oxidoreductase (Complex IV) in liver mitocondrial from rats with hydroxycobalamin [c-lactam]-induced methylmalonic aciduria. J. Biol. Chem. 266:20998–21003.
Lehnert, W., Sperl, W., Suormala, T., and Baumgarther, E.R. (1994). Propionic acidemia: Clinical biochemical and therapeutic aspects. Eur. J. Pediatr. 153(Suppl. 1):S68–S80.
Manson, R.P., Shoemaker, W.J., Shajenko, L., Chambers, T.E., and Herbette, L.G. (1992). Evidence for changes in the Alzheimer's disease brain cortical membrane structure mediated by cholesterol. Neurobiol. Aging 13:413–419.
Matsuishi, T., Stumpf, D.A., Seliem, M., Eguren, L.A., and Chrislip, K. (1991). Proprionate mitochondrial toxicity in liver and skeletal muscle: Acyl Coa levels. Biochem. Med. Metab. Biol. 45:244–253.
Miettinen, T., and Takki-Luukkainem, I.T. (1959). Use of butyl acetate in determination of sialic acid. Acta Chem. Scand. 13:856–858.
Morgan, B.L.G., and Winick, M. (1980). Effects of administration of N-acetylneuraminic acid (NANA) on brain NANA content and behaviour. J. Nutr. 110:416–424.
Nores, G.A., Mitzumari, R.K., and Kremer, D.M. (1994). Chromatographic tank designed to obtain highly reprotucible high-performance thin-layer chromatograms of gangliosides and neutral glycosphingolipds. J. Chromatogr. A 686:155–157.
Ogier, H., Charpentier, C., and Saudubray, J.H. (2000). Organic acidemia. In (J. Fernandes, J.M. Saudubray, and G. Van Der Berghe, eds.), Inborn Metabolic Diseases, 1st edn., Springer, Berlin, pp. 271–299.
Ohtani, Y., Tamai, Y., Ohnuki, Y., and Miura, S. (1996). Ganglioside alterations in the central and peripheral nervous system of patients with Creutzfeldt-Jakob disease. Neurodegeneration 5:331–338.
Qi, Y., and Xue, Q.-M. (1991). Ganglioside levels in hipoxic brains from neonatal and premature infants. Mol. Chem. Neuropathol. 14:87–97.
Rahmann, H. (1995). Brain gangliosides and memory formation. Behav. Brain Res. 66:105–116.
Roodhooft, A.M., Baumgarther, E.R., Martin, J.J., Blom, W., and Van Acker, K.J. (1990). Symmetrical necrosis of the basal ganglia in methylmalonic acidaemia. Eur. J. Pediatr. 149:582–584.
Rösner, H., Al-aqtum, M., and Rahmann, H. (1992). Gangliosides and neuronal diferentiation. Neurochem. Int. 20:339–351.
Schneider, J.S. (1994). The therapeutic role of gangliosides in neurological disorders. CNS Drugs 1:213–222.
Schneider, J.S., Roeltgen, D.P., Mancall, E.L., Chapas-Crilly, J., Rothblat, D.S., and Tatarian, G.T. (1998). Parkinson's disease: Improved function with GM1 ganglioside treatment in a randomized placebo-controlled study. Neurology 50:1630–1636.
Sheikh, K.A., Sun, J.I., Liu, Y., Kawai, H., Crawford, T.O., Proia, R.L., Griffin, J.W., and Schnaar, R.L. (1999). Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc. Natl. Acad. Sci. USA 96:7532–7537.
Skaper, S.D., Leon, A., and Toffano, G. (1989). Ganglioside function in the development and repair of the nervous system: From basic science to clinical application. Mol. Neurobiol. 3:173–199.
Smith, I., and Seakin, S. (1976). Chromatographic and Eletrophoretic Techniques, Vol. 1, 4th edn., Wilian Heinemann Medical Books, pp. 354–356.
Söderberg, M., Edlund, C., Kristensson, K., and Dallner, G. (1991). Fatty acid composition of brain phospholipids in aging and in Alzheimer's disease. Lipids 26:421–425.
Svennerholm, L. (1957). Quantitaive estimation of sialic acids a colorimetric resorcinol-hydrochloric acid method. Bichim. Biophys. Acta 24:604–611.
Svennerholm, L. (1963). Chromathographic separation of human brain gangliosides. J. Neurochem. 10:613–623.
Takamiya, K., Yamamoto, A., Furukawa, K., Yamashiro, S., Shing, M., Okada, M., Fukomoto, S., Haragushi, M., Takeda, N., Fujimura, K., Sakae, M., Kishikawa, M., Shiku, H., Furukawa, K., and Aizawa, S. (1996). Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides but exhibit only subtle defects in their nervous system. Proc. Natl. Acad. Sci. USA 93:10662–10667.
Thomas, P., and Brewer, G.J. (1990). Gangliosides and synaptic transmission. Biochim. Biophys. Acta 1031:277–289.
Toyoshima, S., Watanabe, F., Saido, H., Miyatake, K., and Nakano, Y. (1995). Methylmalonic acid inhibits respiration in rat liver mitochondria. J. Nutr. 125:2846–2850.
Trindade, V.M.T., Perry, M.L.S., and Bernard, E.A. (1992). Gangliosides and sialoproteins in hypothalamus of normal, postnatal, and pre-and postnatal protein undernourished rats. J. Neurol. Sci. 107:93–97.
Trindade, V.M.T., Daniotti, J.L., Raimondi, L., Chazan, R., Netto, C.A., and Maccioni, H.J.F. (2001). Effects of neonatal hypoxia/ischemia on ganglioside expression in the rat hippocampus. Neurochem. Res. 26:591–597.
Vyas, A.A., and Schnaar, R.L. (2001). Brain gangliosides: Functional ligands for myelin stability and the control of nerve regeneration. Biochimie 83:677–682.
Vyas, K.A., Patel, H.V., Vyas, A.A., and Schnaar, R.L. (2001). Segregation of gangliosides GM1 and GD3 on cell membranes, isolated membranes rafts, and defined supported lipid monolayers. Biol. Chem. Hoppe-Seyler 382:241–250.
Wajner, M., Brites, E.C., Dutra, J.C., Buchalter, M.S., Pons, A.H., Pires, R.F., Wannmacher, L.E., Rosa Junior, A., Trindade, V.M.T., and Wannmacher, C.M.D. (1988). Diminished concentrations of ganglioside N-acetylneuraminic acid (G-NeuAc) in cerebellum of young rats receiving chronic administration of methylmalonic acid. J. Neurol. Sci. 85:233–238.
Wajner, M., Dutra, J.C., Cardoso, S.E., Wannmacher, C.M.D., and Motta, E.R. (1992). Effect of methylmalonate on in vitro lactate release and carbon dioxide production by brain of suckling rats. J. Inher. Metab. Dis. 15:92–96.
Wyse, A.T.S., Brusque, A.M., Silva, C.G., Streck, E.L., Wajner, M., and Wannmacher, C.M.D. (1998). Inhibition of Na+, K+-ATPase from rat brain cortex by proprionic acid. NeuroReport 9:1719–1721.
Wyse, A.T.S., Streck, E.L., Barros, S.V.T., Brusque, A.M., Zugno, A.I., and Wajner, M. (2000). Methylmalonate administration decreases Na+, K+-ATPase activity in cerebral cortex of rats. NeuroReport 11:2331–2334.
Yu, R.K., and Ledeen, R.W. (1974). Ganglioside abnormalities in multiple sclerosis. J. Neurochem. 23:169–174.
Yusuf, H.K.M., and Dickerson, J.W.T. (1978). Content and composition of the gangliosides of forebrain, brain stem and cerebellum of the rat during normal and restricted growth. J. Biochem. 84:1501–1506.
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Trindade, V., Brusque, A., Raasch, J. et al. Ganglioside Alterations in the Central Nervous System of Rats Chronically Injected with Methylmalonic and Propionic Acids. Metab Brain Dis 17, 93–102 (2002). https://doi.org/10.1023/A:1015464028616
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DOI: https://doi.org/10.1023/A:1015464028616