Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown


The cellular recycling of glycosphingolipids (GSLs) is mediated by specific lysosomal glycosidases. Inherited deficiencies in these enzymes cause lysosomal storage disorders. Some of the common disorders are Gaucher disease (GD) and Fabry disease (FD) resulting from the defects in lysosomal glucocerebrosidase (GBA) degrading glucosylceramide and α‐galactosidase A (GLA) degrading globotriaosylceramide. Here, GSL accumulation in tissues slows down with age despite ongoing lysosomal turnover of endogenous and endocytosed GSLs. Biochemical adaptations might explain this phenomenon. One crucial adaptation is the deacylation of accumulating GSLs in lysosomes by acid ceramidase. The soluble bases glucosylsphingosine in GD and globotriaosylsphingosine in FD are capable of leaving lysosomes and cells. In the case of GD, a further adaptation involves the cytosol‐faced enzyme GBA2. This enzyme allows extra‐lysosomal degradation of GlcCer while possibly generating glucosylated cholesterol. The beneficial and harmful effects of these adaptations are discussed.

Key Concepts

  • Glycosphingolipids (GSLs) are membrane constituents composed of a ceramide with one or more sugars. The simplest GSL is glucosylceramide (GlcCer).
  • Ongoing recycling of GSLs in cells includes lysosomal degradation by the sequential action of glycosidases and acid ceramidase.
  • Deficiency of lysosomal glycosidase leads to lysosomal storage diseases caused by accumulation of the corresponding substrate in lysosomes. The most common glycosphingolipidoses are Gaucher disease (GD) and Fabry disease (FD).
  • GD is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid β‐glucosidase (glucocerebrosidase; GBA) resulting in lysosomal accumulation of GlcCer. FD is an X‐linked disorder caused by deficient activity of the lysosomal enzyme α‐galactosidase A (GLA) resulting in lysosomal accumulation of globotriaosylceramide (Gb3).
  • Accumulation of storage lipids during GBA and GLA tends to slow down with age, likely partly due to poorly appreciated biochemical adaptations.
  • Active conversion of accumulating GlcCer in lysosomes of GBA‐deficient cells is mediated by acid ceramidase, resulting in the formation of water‐soluble glucosylsphingosine (GlcSph). Likewise, globotriaosylsphingosine (lysoGb3) is formed from accumulating in lysosomes of GLA‐deficient cells.
  • Elevated plasma GlcSph and lysoGb3 levels can be sensitively measured LC–MS and may assist in diagnosing and monitoring of the disease and response to treatment in GD and FD patients, respectively.
  • Increased GlcSph level in GD patients acts as an autoantigen, causing ongoing B‐cell proliferation, leading to multiple myeloma. Increased lysoGb3 level in FD patients is thought to cause damage to nociceptive neurons and podocytes, thus contributing to pain and renal failure.
  • In GD, the cytosol‐faced enzyme β‐glucosidase GBA2 allows degradation of GlcCer outside lysosomes. Through transglycosylation, GBA2 may generate glucosylcholesterol and ceramide from GlcCer and cholesterol.
  • The toxic effects of secondary metabolites such as glycosphingoid bases (GlcSph in GD and lysoGb3 in FD) and glucosylated metabolites (GlcChol in GD) warrant further investigations.

Keywords: lysosome; lysosomal storage disorders; glycosphingolipid; glucocerebrosidase; glucosylsphingosine; Gaucher disease; Fabry disease; lysoGb3

Figure 1. GSL life cycle in the cell. GSLs (black font) are synthesised in the ER (red) and Golgi (yellow) compartments starting with the condensation of serine and palmitoyl‐CoA building blocks. Catabolism of GSLs occurs in lysosomes (grey) through the sequential action of various hydrolases (green font).
Figure 2. AC‐mediated deacylation of GlcCer and Gb3. (a) Deacylation by AC of GlcCer and Gb3 to GlcSph and lysoGb3, respectively. (b) Isoforms of lysoGb3 found in the urine of two classical Fabry patients.
Figure 3. LC‐MS/MS quantification of glycosphingoid bases. (a) 13C5‐encoded isotope standards of GlcSph and lysoGb3. (b) M/z ratio for analyte and internal standard for GlcSph. (c) M/z ratio for analyte and internal standard for lysoGb3. (d) GlcSph levels in GD1 patients (n = 69) and lysoGb3 levels in classical FD patients (n = 20).
Figure 4. GBA2 in silico, in vitro and in vivo. (a) Homology model of GBA2 secondary structure. (b) Chemical structure of nanomolar GBA2 inhibitor AMP‐DNM and activity‐based probe (ABP 1) targeted against GBA and GBA2. (c) Labelling of GBA2 and GBA by ABP 1 and immunoblotting of GBA2 and tubulin in brain homogenates of mice heterozygous, wild‐type and knockout for Gba2. Scale bar = 20 µm. (d) In situ visualisation of GBA2 labelled in vivo following i.c.v. injection of ABP 1. (e) Immunostaining of GBA and GBA2 in the cerebellum of wild‐type mouse. Scale bar = 100 µm.
Figure 5. Transglucosylation. (a) Hydrolysis of GlcCer by a β‐glucosidase yielding free glucose and ceramide. (b) Transglycosylation of cholesterol catalysed by a β‐glucosidase using GlcCer as donor of the glucose moiety and leading to the formation of GlcChol.


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Further Reading

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Sultana S, Reichbauer J, Schüle R, et al. (2015) Lack of enzyme activity in GBA2 mutants associated with hereditary spastic paraplegia/cerebellar ataxia (SPG46). Biochemical and Biophysical Research Communications 465 (1): 35–40.

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Aerts, Johannes M, Ferraz, Maria J, Mirzaian, Mina, Gaspar, Paulo, Oussoren, Saskia V, Wisse, Patrick, Kuo, Chi‐Lin, Lelieveld, Lindsey T, Kytidou, Kassiani, Hazeu, Marc D, Boer, Daphne EC, Meijer, Rianne, van der Lienden, Martijn JC, Chao, Daniela HM, Gabriel, Tanit L, Aten, Jan, Overkleeft, Herman S, van Eijk, Marco, Boot, Rolf G, and Marques, André RA(Oct 2017) Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0027592]