Browsing by Author "van Eijk, Marco"
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- Glycoprotein Non-Metastatic Protein B: an Emerging Biomarker for Lysosomal Dysfunction in MacrophagesPublication . van der Lienden, Martijn; Gaspar, Paulo; Boot, Rolf; Aerts, Johannes; van Eijk, MarcoSeveral diseases are caused by inherited defects in lysosomes, the so-called lysosomal storage disorders (LSDs). In some of these LSDs, tissue macrophages transform into prominent storage cells, as is the case in Gaucher disease. Here, macrophages become the characteristic Gaucher cells filled with lysosomes laden with glucosylceramide, because of their impaired enzymatic degradation. Biomarkers of Gaucher cells were actively searched, particularly after the development of costly therapies based on enzyme supplementation and substrate reduction. Proteins selectively expressed by storage macrophages and secreted into the circulation were identified, among which glycoprotein non-metastatic protein B (GPNMB). This review focusses on the emerging potential of GPNMB as a biomarker of stressed macrophages in LSDs as well as in acquired pathologies accompanied by an excessive lysosomal substrate load in macrophages.
- Lysosomal Storage Diseases. For Better or Worse: Adapting to Defective Lysosomal Glycosphingolipid BreakdownPublication . 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 E.C.; Meijer, Rianne; van der Lienden, Martijn J.C.; Chao, Daniela H.M.; Gabriel, Tanit L.; Aten, Jan; Overkleeft, Herman S.; van Eijk, Marco; Boot, Rolf G.; Marques, André R.A.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.