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Journal of Lipid Research, Vol. 46, 744-751, April 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice

J. L. Kasperzyk, A. d'Azzo, F. M. Platt, J. Alroy and T. N. Seyfried¹

Department of Biology, Boston College, Chestnut Hill, MA 02467

¹ To whom correspondence should be addressed. e-mail: thomas.seyfried{at}bc.edu

II³NeuAc-GgOse₄Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid ß-galactosidase (ß-gal), resulting in the accumulation of ganglioside GM1 and its asialo derivative GgOse₄Cer (GA1) in the central nervous system, primarily in the brain. In this study, we investigated the effects of N-butyldeoxygalacto-nojirimycin (N B-DGJ), an imino sugar that inhibits ganglioside biosynthesis, in normal C57BL/6J mice and in ß-gal knockout (ß-gal^–/–) mice from postnatal day 9 (p-9) to p-15. This is a period of active cerebellar development and central nervous system (CNS) myelinogenesis in the mouse and would be comparable to late-stage embryonic and early neonatal development in humans. N B-DGJ significantly reduced total ganglioside and GM1 content in cerebrum-brainstem (C-BS) and in cerebellum of normal and ß-gal^–/– mice. N B-DGJ had no adverse effects on body weight or C-BS/cerebellar weight, water content, or thickness of the external cerebellar granule cell layer. Sphingomyelin was increased in C-BS and cerebellum, but no changes were found for cerebroside (a myelin-enriched glycosphingolipid), neutral phospholipids, or GA1 in the treated mice.

Our findings indicate that the effects of N B-DGJ in the postnatal CNS are largely specific to gangliosides and suggest that N B-DGJ may be an effective early intervention therapy for GM1 gangliosidosis and other ganglioside storage disorders.

Supplementary key words N-butyldeoxygalactonojirimycin • II³ (NeuAc)₂-LacCer • II³NeuAc-GgOse₄Cer • asialo derivative • myelin • cerebrosides • granule cells • neurodegeneration

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