title: Phospholipid synthesis is decreased in neuronal tissue in a mouse model of Sandhoff disease.
abstract: Sandhoff disease is a progressive neurodegenerative disorder caused by mutations in the HEXB gene which encodes for the beta-subunit of beta-hexosaminidase A and B, resulting in ganglioside GM(2) accumulation in the brain. We now demonstrate that phospholipid metabolism is altered in both cultured neurons and in brain tissue from a mouse model of Sandhoff disease, the Hexb-/- mouse. Metabolic labelling using [methyl-(14)C]choline and l-[3-(3)H]serine demonstrated reduced incorporation of [methyl-(14)C]choline into phospholipids in brain tissue but not in liver or spleen. Phospholipid mass was also reduced in brain. The activities of CTP : phosphocholine cytidylyltransferase (CCT) and phosphatidylserine synthase were also reduced in brain tissue from Hexb-/- mice, probably because of post-translational modification as no changes were observed in levels of enzyme expression. The relevance of these findings to Sandhoff disease in human patients is strengthened by observations made over 30 years ago on autopsy tissue of Tay Sachs and Sandhoff disease patients, in which reduced phospholipid levels were observed. We suggest that changes in phospholipid metabolism are not simply because of loss of neuronal tissue as a result of degeneration but rather may cause degeneration, and we discuss the possible effects that changes in phospholipid metabolism could play in the neuropathophysiology of Sandhoff disease.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Buccoliero
authors.forename: Jacques
authors.initials: J
authors.lastname: Bodennec
authors.forename: Gerhild
authors.initials: G
authors.lastname: Van Echten-Deckert
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D010717:CDPdiacylglycerol-Serine O-Phosphatidyltransferase / Q000378:metabolism; D002250:Carbon Radioisotopes; D002478:Cells, Cultured; D002794:Choline / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics; D019916:Choline-Phosphate Cytidylyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D054819:Hexosaminidase B; D006624:Hippocampus / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism*; D009928:Organ Specificity; D010743:Phospholipids / Q000096:biosynthesis / Q000378:metabolism*; D012497:Sandhoff Disease / Q000378:metabolism*; D012694:Serine / Q000378:metabolism / Q000493:pharmacokinetics; D013154:Spleen / Q000378:metabolism; D014316:Tritium; D001619:beta-N-Acetylhexosaminidases / Q000172:deficiency / Q000235:genetics
chemical_list: D002250:Carbon Radioisotopes; D010743:Phospholipids; C017506:methylcholine; D014316:Tritium; D012694:Serine; D019916:Choline-Phosphate Cytidylyltransferase; D010717:CDPdiacylglycerol-Serine O-Phosphatidyltransferase; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases; D002794:Choline