Death by Ganglioside: A SERCA-uitous Route

Abstract

The GM2 gangliosidoses, which include Tay-Sachs disease and Sandhoff disease, are a group of inherited neurodegenerative disorders in which lysosomal degradation of gangliosides is reduced so that neuronal ganglioside GM2 (GM2) accumulates. The mechanisms whereby GM2 accumulation leads to neuronal death are unknown. Pelled et al. investigated the effects of GM2 accumulation in a strain of mutant mice (Hexb –/– mice) that lack the HEXB gene (which codes for a subunit of β-hexosaminidase) and serve as a mouse model of Sandhoff disease. Microsomes made from the brains of mutant mice showed GM2 accumulation; this accumulation was reduced in mice fed with N -butyldeoxynojirimycin (NB-DNJ), which inhibits glycolipid synthesis. Using spectrophotometric analysis with the calcium (Ca 2+ )-sensitive dye antipyrylazo III, the authors showed that Ca 2+ uptake was reduced in microsomes from the Hexb –/– mice as well as in microsomes from wild-type mice that were incubated with GM2. The V max of the sarcoendoplasmic reticulum Ca 2+ -adenosine 5'-triphosphatase (SERCA) for Ca 2+ accumulation was reduced with no effect on SERCA affinity for Ca 2+ , or brain levels of SERCA mRNA or protein. Microsomes from Hexb –/– showed increased sensitivity to Ca 2+ -induced Ca 2+ release and greater sensitivity to the SERCA inhibitor thapsigargin; feeding the mutant mice NB-DNJ abolished these effects. Neurons cultured from embryonic Hexb –/– mice showed decreased uptake of 45 Ca 2+ and were more sensitive to thapsigargin-mediated cell death. Thus, alterations in intracellular Ca 2+ handling may play a role in the mechanism whereby GM2 leads to neurodegeneration. D. Pelled, E. Lloyd-Evans, C. Riebeling, M. Jeyakumar, F. M. Platt, A. H. Futerman, Inhibition of calcium uptake via the sarco/endoplasmic reticulum Ca 2+ -ATPase in a mouse model of Sandhoff disease and prevention by treatment with N -butyldeoxynojirimycin. J. Biol. Chem . 278 , 29496-29501 (2003). [Abstract] [Full Text]