Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid Breakdown
Authors: 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 , Marques André RA 
Published: October 2017

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.