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

Abstract

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.

Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

“…Likewise, excessive globotriaosylsphingosine (lyso-Gb3) in Fabry patients is thought to contribute to neuronopathic pain and loss of podocytes [39,40]. It is of interest to point out that apparently a dysfunction in lysosomal catabolism of glycosphingolipids leads to metabolic adaptations, generating secondary metabolites that ultimately may cause specific symptoms beyond the storage cells [41]. A recently recognized glycolipid abnormality in GD patients concerns glucosylcholesterol (GlcChol): it appears that glucosylcholesterol is formed in cells by sequential action of the enzymes glucosylceramide synthase (GCS) and the transglucosylating non-lysosomal GBA variant GBA2 [42].…”

“…Corrections of Gaucher cell markers are also monitored in GD patients treated by means of substrate reduction therapy (SRT). In this alternative therapeutic approach, an inhibitor of GCS is orally administered to GD patients to reduce the endogenous synthesis of GlcCer and thus balance the impaired capacity of lysosomal degradation of the lipid [41]. Registered for SRT of type 1 GD are at present two GCS inhibitors miglustat and eliglustat [92,93,94]; responses in CHIT1, CCL18 and GlcSph to the SRT therapies have been analyzed [95].…”

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

“…Moreover, increased substrate levels may drive lysosomal enzymes to form 'rare' metabolites. For example, in NPC, intralysosomal accumulation of cholesterol and glucosylceramide leads to the formation of glucosylated cholesterol (Marques et al, 2016), a metabolite that may play a role in pathology (Aerts et al, 2017;Franco et al, 2018). It is possible that a number of further metabolites arise that could contribute to disease progression.…”

“…GD patients show increased susceptibility to monoclonal and polyclonal gammopathies due to the production of antibodies directed against accumulating lysosphingolipids (Nair et al, 2016;Pastores and Hughes, 2017;Pavlova et al, 2013). Because increased levels of lysosphingolipids are not exclusive to GD, it is possible that patients with other LSDs may also be more prone to develop malignancies due to the production of antibodies against these lipids (Aerts et al, 2017).…”

Lysosome (Dys)function in Atherosclerosis—A Big Weight on the Shoulders of a Small Organelle

“…Substrate reduction therapy (SRT) is an alternative therapeutic approach often employed in LSDs whenever treatment by ERT is not feasible. Approved SRT strategies involve the pharmacological inhibition of the synthesis of glycosphingolipids (GSLs), a class of membrane lipids that undergo lysosomal breakdown and that is often a primary or secondary storage product of LSDs ( Aerts et al, 2017 ; Platt, 2018 ). Multiple GSLs, such as the building block ceramide, are bioactive lipids, and impairment of their degradation may thus have considerable consequences for pathological processes.…”