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.
Pubmed ID: 8789434 RIS Download
Animals | Base Sequence | Brain Chemistry | Brain Injuries | Disease Models, Animal | Female | G(M2) Ganglioside | Gene Targeting | Glycosphingolipids | Hexosaminidase A | Hexosaminidase B | Humans | Liver | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Molecular Sequence Data | Organ Specificity | Phenotype | RNA, Messenger | Sandhoff Disease | Spinal Cord | Tay-Sachs Disease | beta-N-Acetylhexosaminidases