Dramatically Different Phenotypes in Mouse Models of Human Tay-Sachs and Sandhoff Diseases Academic Article uri icon

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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

  • Phaneuf, D
  • Wakamatsu, N
  • Huang, J-Q
  • Borowski, A
  • Peterson, AC
  • Fortunato, SR
  • Ritter, G
  • Igdoura, Suleiman
  • Morales, CR
  • Benoit, G
  • Akerman, BR
  • Leclerc, D
  • Hanai, N
  • Marth, JD
  • Trasler, JM
  • Gravel, RA

publication date

  • January 1, 1996

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