title: Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice.
abstract: II3NeuAc-GgOse4Cer (GM1) gangliosidosis is an incurable lysosomal storage disease caused by a deficiency in acid beta-galactosidase (beta-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 beta-gal knockout (beta-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 beta-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.
authors.affiliation: Department of Biology, Boston College, Chestnut Hill, MA 02467, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Kasperzyk
authors.forename: A
authors.initials: A
authors.lastname: d'Azzo
authors.forename: F M
authors.initials: FM
authors.lastname: Platt
authors.forename: J
authors.initials: J
authors.lastname: Alroy
authors.forename: T N
authors.initials: TN
authors.lastname: Seyfried
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001933:Brain Stem / Q000378:metabolism*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002855:Chromatography, Thin Layer; D005732:Gangliosides / Q000378:metabolism*; D016537:Gangliosidosis, GM1 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D013109:Sphingomyelins / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D005732:Gangliosides; D013109:Sphingomyelins; D017485:1-Deoxynojirimycin; C090092:migalastat