title: N-butyldeoxygalactonojirimycin reduces brain ganglioside and GM2 content in neonatal Sandhoff disease mice.
abstract: Sandhoff disease involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the beta-subunit gene of beta-hexosaminidase A and B (Hexb gene). Accumulation of these glycosphingolipids (GSLs) produces progressive neurodegeneration, ultimately leading to death. Substrate reduction therapy (SRT) aims to decrease the rate of glycosphingolipid (GSL) biosynthesis to compensate for the impaired rate of catabolism. The imino sugar, N-butyldeoxygalactonojirimycin (NB-DGJ) inhibits the first committed step in GSL biosynthesis. NB-DGJ treatment, administered from postnatal day 2 (p-2) to p-5 (600 mg/kg/day)), significantly reduced total brain ganglioside and GM2 content in the Sandhoff disease (Hexb(-/-)) mice, but did not reduce the content of GA2. We also found that NB-DGJ treatment caused a slight, but significant elevation in brain sialidase activity. The drug had no adverse effects on viability, body weight, brain weight, or brain water content in the mice. No significant alterations in neutral lipids or acidic phospholipids were observed in the NB-DGJ-treated Hexb(-/-) mice. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM2 content at early neonatal ages.
authors.affiliation: Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA 02467, USA.
authors.forename: Rena C
authors.initials: RC
authors.lastname: Baek
authors.forename: Julie L
authors.initials: JL
authors.lastname: Kasperzyk
authors.forename: Frances M
authors.initials: FM
authors.lastname: Platt
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Seyfried
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D005678:G(M2) Ganglioside / Q000235:genetics / Q000378:metabolism*; D005732:Gangliosides / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D009439:Neuraminidase / Q000187:drug effects / Q000378:metabolism; D012497:Sandhoff Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D016896:Treatment Outcome; D054820:beta-Hexosaminidase alpha Chain / Q000235:genetics
chemical_list: D005732:Gangliosides; D006028:Glycosphingolipids; D017485:1-Deoxynojirimycin; D005678:G(M2) Ganglioside; C090092:migalastat; D009439:Neuraminidase; D054820:beta-Hexosaminidase alpha Chain