Abstract
Sandhoff disease (SD) is a glycosphingolipid (GSL) storage disease that arises from an autosomal recessive mutation in the gene for the β-subunit of β-Hexosaminidase A (Hexb gene), which catabolizes ganglioside GM2 within lysosomes. Accumulation of GM2 and asialo-GM2 (GA2) occurs primarily in the CNS, leading to neurodegeneration and brain dysfunction. We analyzed the total lipids in the brains of SD mice, cats, and humans. GM2 and GA2 were mostly undetectable in the normal mouse, cat, and human brain. The lipid abnormalities in the SD cat brain were generally intermediate to those observed in the SD mouse and the SD human brains. GM2 comprised 38, 67, and 87% of the total brain ganglioside distribution in the SD mice, cats, and humans, respectively. The ratio of GA2–GM2 was 0.93, 0.13, and 0.27 in the SD mice, cats, and humans, respectively, suggesting that the relative storage of GA2 is greater in the SD mouse than in the SD cat or human. Finally, the myelin-enriched lipids, cerebrosides and sulfatides, were significantly lower in the SD brains than in the control brains. This study is the first comparative analysis of brain lipids in mice, cats, and humans with SD and will be important for designing therapies for Sandhoff disease patients.
Similar content being viewed by others
Abbreviations
- CHCl3 :
-
Chloroform
- CNS:
-
Central nervous system
- GA2:
-
Asialo-GM2
- GSL:
-
Glycosphingolipid
- HexA:
-
β-Hexosaminidase A
- HPTLC:
-
High-performance thin-layer chromatograph
- MeOH:
-
Methanol
- SD:
-
Sandhoff disease
References
Neufeld EF (1991) Lysosomal storage diseases. Annu Rev Biochem 60:257–280
Gravel RA, Clarke JTR, Kaback MM, Mahuran D, Sandhoff K, Suzuki K (1995) The GM2 gangliosidoses. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 7th edn. McGraw-Hill, New York
Chavany C, Jendoubi M (1998) Biology and potential strategies for the treatment of GM2 gangliosidoses. Mol Med Today 4:158–165
Jeyakumar M, Smith DA, Williams I, Borja MC, Neville DCA, Butters TD, Dwek RA, Platt FM (2004) Anti-inflammatory and anti-oxidant therapies increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin. Ann Neurology 56:642–649
Jeyakumar M, Butters TD, Dwek RA, Platt FM (2002) Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis. Neuropathol Appl Neurobiol 28:343–357
Schiffmann R, Brady RO (2002) New prospects for the treatment of lysosomal storage diseases. Drugs 62:733–742
Lee JP, Jeyakumar M, Gonzalez R, Takahashi H, Lee PJ, Baek RC, Clark D, Rose H, Fu G, Clarke J, McKercher S, Meerloo J, Muller FJ, Park KI, Butters TD, Dwek RA, Schwartz P, Tong G, Wenger D, Lipton SA, Seyfried TN, Platt FM, Snyder EY (2007) Stem cells act through multiple mechanisms to benefit mice with neurodegenerative metabolic disease. Nat Med 13:439–447
Andersson U, Smith D, Jeyakumar M, Butters TD, Borja MC, Dwek RA, Platt FM (2004) Improved outcome of N-butyldeoxygalactonojirimycin-mediated substrate reduction therapy in a mouse model of Sandhoff disease. Neurobiol Dis 16:506–515
Cachon-Gonzalez MB, Wang SZ, Lynch A, Ziegler R, Cheng SH, Cox TM (2006) Effective gene therapy in an authentic model of Tay-Sachs-related diseases. Proc Natl Acad Sci USA 103:10373–10378
Norflus F, Tifft CJ, McDonald MP, Goldstein G, Crawley JN, Hoffmann A, Sandhoff K, Suzuki K, Proia RL (1998) Bone marrow transplantation prolongs life span and ameliorates neurologic manifestations in Sandhoff disease mice. J Clin Invest 101:1881–1888
Denny CA, Kasperzyk JL, Gorham KN, Bronson RT, Seyfried TN (2006) Influence of caloric restriction on motor behavior, longevity, and brain lipid composition in Sandhoff disease mice. J Neurosci Res 83:1028–1038
Baek RC, Kasperzyk JL, Platt FM, Seyfried TN (2008) N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice. Neurochem Int 52:1125–1133
Haug H (1987) Brain sizes, surfaces, and neuronal sizes of the cortex cerebri: a stereological investigation of man and his variability and a comparison with some mammals (primates, whales, marsupials, insectivores, and one elephant). Am J Anat 180:126–142
Roth G, Dicke U (2005) Evolution of the brain and intelligence. Trends Cogn Sci 9:250–257
Hofman MA (1984) Energy metabolism and relative brain size in human neonates from single and multiple gestations. An allometric study. Biol Neonate 45:157–164
Martin DR, Krum BK, Varadarajan GS, Hathcock TL, Smith BF, Baker HJ (2004) An inversion of 25 base pairs causes feline GM2 gangliosidosis variant. Exp Neurol 187:30–37
Baker HJ, Reynolds GD, Walkley SU, Cox NR, Baker GH (1979) The gangliosidoses: comparative features and research applications. Vet Pathol 16:635–649
Cork LC, Munnell JF, Lorenz MD (1978) The pathology of feline GM2 gangliosidosis. Am J Pathol 90:723–734
Cork LC, Munnell JF, Lorenz MD, Murphy JV, Baker HJ, Rattazzi MC (1977) GM2 ganglioside lysosomal storage disease in cats with beta-hexosaminidase deficiency. Science 196:1014–1017
Sango K, Yamanaka S, Hoffmann A, Okuda Y, Grinberg A, Westphal H, McDonald MP, Crawley JN, Sandhoff K, Suzuki K, Proia RL (1995) Mouse models of Tay-Sachs and Sandhoff diseases differ in neurologic phenotype and ganglioside metabolism. Nat Genet 11:170–176
Sandhoff K, Harzer K, Wassle W, Jatzkewitz H (1971) Enzyme alterations and lipid storage in three variants of Tay-Sachs disease. J Neurochem 18:2469–2489
Rosengren B, Mansson JE, Svennerholm L (1987) Composition of gangliosides and neutral glycosphingolipids of brain in classical Tay-Sachs and Sandhoff disease: more lyso-GM2 in Sandhoff disease? J Neurochem 49:834–840
Galjaard H (1980) Genetic metabolic disease: diagnosis and prenatal analysis. Elsevier, Amsterdam
Hauser EC, Kasperzyk JL, d’Azzo A, Seyfried TN (2004) Inheritance of lysosomal acid b-galactosidase activity and gangliosides in crosses of DBA/2 J and knockout mice. Biochem Genet 42:241–257
Seyfried TN, Glaser GH, Yu RK (1978) Cerebral, cerebellar, and brain stem gangliosides in mice susceptible to audiogenic seizures. J Neurochem 31:21–27
Kasperzyk JL, El-Abbadi MM, Hauser EC, D’Azzo A, Platt FM, Seyfried TN (2004) N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J Neurochem 89:645–653
Macala LJ, Yu RK, Ando S (1983) Analysis of brain lipids by high performance thin-layer chromatography and densitometry. J Lipid Res 24:1243–1250
Folch J, Lees M, Sloane-Stanley GH (1957) A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 226:497–509
Kasperzyk JL, d’Azzo A, Platt FM, Alroy J, Seyfried TN (2005) Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice. J Lipid Res 46:744–751
Ando S, Chang NC, Yu RK (1978) High-performance thin-layer chromatography and densitometric determination of brain ganglioside compositions of several species. Anal Biochem 89:437–450
Seyfried TN, Bernard D, Mayeda F, Macala L, Yu RK (1984) Genetic analysis of cerebellar lipids in mice susceptible to audiogenic seizures. Exp Neurol 84:590–595
Seyfried TN, Yu RK, Miyazawa N (1982) Differential cellular enrichment of gangliosides in the mouse cerebellum: analysis using neurological mutants. J Neurochem 38:551–559
Seyfried TN, Yu RK (1985) Ganglioside GD3: structure, cellular distribution, and possible function. Mol Cell Biochem 68:3–10
Li SC, Li YT, Moriya S, Miyagi T (2001) Degradation of G(M1) and G(M2) by mammalian sialidases. Biochem J 360:233–237
Yuziuk JA, Bertoni C, Beccari T, Orlacchio A, Wu YY, Li SC, Li YT (1998) Specificity of mouse GM2 activator protein and beta-N-acetylhexosaminidases A and B. Similarities and differences with their human counterparts in the catabolism of GM2. J Biol Chem 273:66–72
Bertoni C, Li YT, Li SC (1999) Catabolism of asialo-GM2 in man and mouse. Specificity of human/mouse chimeric GM2 activator proteins. J Biol Chem 274:28612–28618
Kroll RA, Pagel MA, Roman-Goldstein S, Barkovich AJ, D’Agostino AN, Neuwelt EA (1995) White matter changes associated with feline GM2 gangliosidosis (Sandhoff disease): correlation of MR findings with pathologic and ultrastructural abnormalities. AJNR Am J Neuroradiol 16:1219–1226
Folkerth RD, Alroy J, Bhan I, Kaye EM (2000) Infantile G(M1) gangliosidosis: complete morphology and histochemistry of two autopsy cases, with particular reference to delayed central nervous system myelination. Pediatr Dev Pathol 3:73–86
Kaye EM, Alroy J, Raghavan SS, Schwarting GA, Adelman LS, Runge V, Gelblum D, Thalhammer JG, Zuniga G (1992) Dysmyelinogenesis in animal model of GM1 gangliosidosis. Pediatr Neurol 8:255–261
Pellkofer R, Jatzkewitz H (1974) The enzymic degradation of cerebrosides and sulphatides in human demyelination due to disseminated sclerosis and encephalitis, and to Tay-Sachs disease. Acta neuropathologica 29:25–35
van der Voorn JP, Pouwels PJ, Kamphorst W, Powers JM, Lammens M, Barkhof F, van der Knaap MS (2005) Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders. AJNR Am J Neuroradiol 26:442–446
Vite CH, Magnitsky S, Aleman D, O’Donnell P, Cullen K, Ding W, Pickup S, Wolfe JH, Poptani H (2007) apparent diffusion coefficient reveals gray and white matter disease, and t2 mapping detects white matter disease in the brain in feline alpha-mannosidosis. AJNR Am J Neuroradiol
McNally MA, Baek RC, Avila RL, Seyfried TN, Strichartz GR, Kirschner DA (2007) Peripheral nervous system manifestations in a Sandhoff disease mouse model: nerve conduction, myelin structure, lipid analysis. J Negat Results Biomed 6:8
Denny CA, Alroy J, Pawlyk BS, Sandberg MA, d’Azzo A, Seyfried TN (2007) Neurochemical, morphological, and neurophysiological abnormalities in retinas of Sandhoff and GM1 gangliosidosis. J Neurochem 101:1294–1302
Acknowledgments
We acknowledge the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore (NICHD contract # N01-HD-4-3368 and N01-HD-4-3383) for the human tissue samples. This work was supported in part from NIH grant (NS055195), the National Tay-Sachs and Allied Disease Association, and from the Lysosomal Storage Disease Research Consortium.
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Baek, R.C., Martin, D.R., Cox, N.R. et al. Comparative Analysis of Brain Lipids in Mice, Cats, and Humans with Sandhoff Disease. Lipids 44, 197–205 (2009). https://doi.org/10.1007/s11745-008-3268-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11745-008-3268-0