title: Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases.
abstract: We have generated mouse models of human Tay-Sachs and Sandhoff diseases by targeted disruption of the Hexa (alpha subunit) or Hexb (beta subunit) genes, respectively, encoding lysosomal beta-hexosaminidase A (structure, alpha) and B (structure, beta beta). Both mutant mice accumulate GM2 ganglioside in brain, much more so in Hexb -/- mice, and the latter also accumulate glycolipid GA2. Hexa -/- mice suffer no obvious behavioral or neurological deficit, while Hexb -/- mice develop a fatal neurodegenerative disease, with spasticity, muscle weakness, rigidity, tremor and ataxia. The Hexb -/- but not the Hexa -/- mice have massive depletion of spinal cord axons as an apparent consequence of neuronal storage of GM2. We propose that Hexa -/- mice escape disease through partial catabolism of accumulated GM2 via GA2 (asialo-GM2) through the combined action of sialidase and beta-hexosaminidase B.
authors.affiliation: Department of Pediatrics, McGill University, Montreal, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Phaneuf
authors.forename: N
authors.initials: N
authors.lastname: Wakamatsu
authors.forename: J Q
authors.initials: JQ
authors.lastname: Huang
authors.forename: A
authors.initials: A
authors.lastname: Borowski
authors.forename: A C
authors.initials: AC
authors.lastname: Peterson
authors.forename: S R
authors.initials: SR
authors.lastname: Fortunato
authors.forename: G
authors.initials: G
authors.lastname: Ritter
authors.forename: S A
authors.initials: SA
authors.lastname: Igdoura
authors.forename: C R
authors.initials: CR
authors.lastname: Morales
authors.forename: G
authors.initials: G
authors.lastname: Benoit
authors.forename: B R
authors.initials: BR
authors.lastname: Akerman
authors.forename: D
authors.initials: D
authors.lastname: Leclerc
authors.forename: N
authors.initials: N
authors.lastname: Hanai
authors.forename: J D
authors.initials: JD
authors.lastname: Marth
authors.forename: J M
authors.initials: JM
authors.lastname: Trasler
authors.forename: R A
authors.initials: RA
authors.lastname: Gravel
mesh_terms: D000818:Animals; D001483:Base Sequence; D001923:Brain Chemistry; D001930:Brain Injuries; D004195:Disease Models, Animal; D005260:Female; D005678:G(M2) Ganglioside / Q000032:analysis; D018390:Gene Targeting; D006028:Glycosphingolipids / Q000032:analysis; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D006801:Humans; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D012497:Sandhoff Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013116:Spinal Cord / Q000473:pathology; D013661:Tay-Sachs Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001619:beta-N-Acetylhexosaminidases / Q000235:genetics* / Q000378:metabolism
chemical_list: D006028:Glycosphingolipids; D012333:RNA, Messenger; D005678:G(M2) Ganglioside; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases