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Review
. 2021 Feb;132(2):59-75.
doi: 10.1016/j.ymgme.2020.12.291. Epub 2020 Dec 29.

Gaucher disease: Basic and translational science needs for more complete therapy and management

Gregory A Grabowski  1 , Armand H M Antommaria  2 , Edwin H Kolodny  3 , Pramod K Mistry  4
Affiliations
Review

Gaucher disease: Basic and translational science needs for more complete therapy and management

Gregory A Grabowski et al. Mol Genet Metab. 2021 Feb.
No abstract available

Keywords: Enzymology; Genetic counseling; Innate Immunity; Lysosomal storage disease; Parkinson disease.

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Conflict of interest statement

Declaration of Competing Interest The authors declare no conflicts of interest.

Figures

Figure 1:
Figure 1:
Schematic of myeloid cell ontogeny and development from the yolk-sac or bone marrow stem cells. Through complex lineage specification, several visceral organs derive resident myeloid cells from precursors originating in the fetal liver or yolk-sac, e.g., microglia and PVM of Virchow-Robinow spaces of blood vessels in the brain. Each of these has unique properties and gene expression profiles that differ from other tissue macrophages. Similarly, bone marrow-derived myeloid cells undergo complex differentiation with major roles in the innate and adaptive immune systems, including elicitation of anti-GC antibodies in GD with activation of the C5a/C5aR1 complement axis. Osteoclasts have primary functions in bone resorption and remodeling.
Figure 2:
Figure 2:
Schematic of the stress responses of cells to untreated Gaucher disease. The specific cellular response varies with cell type, but innate immune cells (macrophages of various ontogenies, microglia, and dendritic cells) evoke many of the indicated pathways leading to multiple different types of programmed cell death. The major features result from lysosomal stresses due to excess GCs ad GSs leading to disruption of the autophagy/lysosomal system from destabilization of the lysosomal and autophagosome membranes. Such disruption leads to dissociation of mTORC1 from the lysosomal membrane making it inactivate for the phosphorylation of TFEB/TFE3. These factors then enter the nucleus and activate the transcription of genes involved in autophagic, lysosomal biogenesis and enzymes, peroxisomal biogenesis and enzymes while the pathways for lipogenesis and adipogenesis are blocked by in inactivation of Lipin 1. Components of the mitochondria are also disrupted with resultant disruption of the oxidative pathways (not shown). The overall effects lead directly or indirectly to proinflammatory activation through cell dependent cell death pathways. The damage to various organellar membranes is shown as dashed circles and the resultant effects on substrates and precursors are shown in dashed lines. The diminished or altered function of the various organellar pathways indicate the degrees of metabolic disturbance. Dissection of these cellular-specific pathway abnormalities should provide for identification of potential modifiers of GD expression within and among phenotypes.
Figure 3:
Figure 3:
Age at diagnosis or detection (years) of GD 1 individuals stratified by genotype based on allele specific analyses. The numbers of patients and mean/median ages are shown on the right for each genotype. The RED box indicates the potential mis-genotyping due to the Δ55 deletion in Exon 9 that would prevent appropriate binding of the primer specific for the N370S allele. The correct genotype in such a case would be N370S/Δ55 corresponding to a protein type of p.N370S/Null, similar to 84GG. The dots represent individual patients. The 1st and 3rd quartiles are upper and lower bounds of the boxes, respectively. The horizontal lines within the boxes are the median values.
See this image and copyright information in PMC

References

    1. Boer DEC, van Smeden J, Bouwstra JA, and Aerts J. Glucocerebrosidase: Functions in and Beyond the Lysosome. J Clin Med. 2020;9(3). - PMC - PubMed
    1. Wei RR, Hughes H, Boucher S, Bird JJ, Guziewicz N, Van Patten SM, et al. X-ray and biochemical analysis of N370S mutant human acid β-glucosidase. J Biol Chem. 2011;286(1):299–308. - PMC - PubMed
    1. Lieberman RL, D’Aquino JA, Ringe D, and Petsko GA. Effects of pH and iminosugar pharmacological chaperones on lysosomal glycosidase structure and stability. Biochemistry. 2009;48(22):4816–27. - PMC - PubMed
    1. Brumshtein B, Greenblatt HM, Butters TD, Shaaltiel Y, Aviezer D, Silman I, et al. Crystal structures of complexes of N-butyl- and N-nonyl-deoxynojirimycin bound to acid β-glucosidase: insights into the mechanism of chemical chaperone action in Gaucher disease. J Biol Chem. 2007;282(39):29052–8. - PubMed
    1. Dvir H, Harel M, McCarthy AA, Toker L, Silman I, Futerman AH, et al. X-ray structure of human acid-β-glucosidase, the defective enzyme in Gaucher disease. EMBO Rep. 2003;4(7):704–9. - PMC - PubMed

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