2013
DOI: 10.1371/journal.pone.0057560
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Substrate Compositional Variation with Tissue/Region and Gba1 Mutations in Mouse Models–Implications for Gaucher Disease

Abstract: Gaucher disease results from GBA1 mutations that lead to defective acid β-glucosidase (GCase) mediated cleavage of glucosylceramide (GC) and glucosylsphingosine as well as heterogeneous manifestations in the viscera and CNS. The mutation, tissue, and age-dependent accumulations of different GC species were characterized in mice with Gba1 missense mutations alone or in combination with isolated saposin C deficiency (C*). Gba1 heteroallelism for D409V and null alleles (9V/null) led to GC excesses primarily in th… Show more

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Cited by 42 publications
(47 citation statements)
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“…The levels of GlcSph have been shown to be increased in human GD brains and GD mouse models . GlcSph was unaffected in the putamen and cerebellum of PD+GBA and sporadic PD brains, when compared with control.…”
Section: Resultsmentioning
confidence: 96%
See 1 more Smart Citation
“…The levels of GlcSph have been shown to be increased in human GD brains and GD mouse models . GlcSph was unaffected in the putamen and cerebellum of PD+GBA and sporadic PD brains, when compared with control.…”
Section: Resultsmentioning
confidence: 96%
“…The mechanism by which loss of GCase activity affects the ALP is unclear. The accumulation of GlcCer or glucosylsphingosine (GlcSph; deacetylated GlcCer) could contribute to lysosomal dysfunction and toxicity, and so to the pathogenesis of PD in GBA1 mutation carriers . However, although PD+GBA brains have significant loss of GCase activity, the residual function of the enzyme may be sufficient to prevent substrate accumulation.…”
mentioning
confidence: 99%
“…Frozen cell pellets were shipped on dry ice to Cincinnati Children’s Hospital for glucosylsphingosine analysis. Lipid extraction and LC–MS/MS analysis of glucosylsphingosine accumulation was performed as previously described (Sun et al, 2012, 2013). All quantitative glucosylsphingosine data was normalized to total protein detected in the cell lysate.…”
Section: Methodsmentioning
confidence: 99%
“…Intensities of the secondary ions relating to psychosine (m/z 462-N264, 282, 444) and the ISTD (m/z 490-N 292, 294, 310, 472) were summed up, and the response ratios were calculated, which were then compared to calibration curves derived from addition of psychosine standard (0-8 nmol) and ISTD (1 nmol) to brain tissue of wild type mice before extraction. It has to be mentioned, that this method cannot distinguish psychosine from its epimer glucosylsphingosine, which is, however, of very low abundance in tissues unless β-glucocerebrosidase or saposin C is deficient (Sun et al, 2013).…”
Section: Psychosine Quantificationmentioning
confidence: 99%