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

• Autor(a) principal: Aerts, Johannes M.
• Data de Publicação: 2017
• Outros Autores: 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.
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.18/5477
• topic: Lysosome; Lysosomal Storage Disorders; Glycosphingolipid; Glucocerebrosidase; Glucosylsphingosine; Gaucher Disease; Fabry Dsease; LysoGb3; Doenças Genéticas

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.