Dramatically different phenotypes in mouse models of human Tay-Sachs and Sandhoff diseases.
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.
Phaneuf
D
D
Department of Pediatrics, McGill University, Montreal, Canada.
Wakamatsu
N
N
Huang
J Q
JQ
Borowski
A
A
Peterson
A C
AC
Fortunato
S R
SR
Ritter
G
G
Igdoura
S A
SA
Morales
C R
CR
Benoit
G
G
Akerman
B R
BR
Leclerc
D
D
Hanai
N
N
Marth
J D
JD
Trasler
J M
JM
Gravel
R A
RA
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
D006028:Glycosphingolipids; D012333:RNA, Messenger; D005678:G(M2) Ganglioside; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases