Sphingolipid lysosomal storage diseases: from bench to bedside

Abstract

Johann Ludwig Wilhelm Thudicum described sphingolipids (SLs) in the late nineteenth century, but it was only in the past fifty years that SL research surged in importance and applicability. Currently, sphingolipids and their metabolism are hotly debated topics in various biochemical fields. Similar to other macromolecular reactions, SL metabolism has important implications in health and disease in most cells. A plethora of SL-related genetic ailments has been described. Defects in SL catabolism can cause the accumulation of SLs, leading to many types of lysosomal storage diseases (LSDs) collectively called sphingolipidoses. These diseases mainly impact the neuronal and immune systems, but other systems can be affected as well. This review aims to present a comprehensive, up-to-date picture of the rapidly growing field of sphingolipid LSDs, their etiology, pathology, and potential therapeutic strategies. We first describe LSDs biochemically and briefly discuss their catabolism, followed by general aspects of the major diseases such as Gaucher, Krabbe, Fabry, and Farber among others. We conclude with an overview of the available and potential future therapies for many of the diseases. We strive to present the most important and recent findings from basic research and clinical applications, and to provide a valuable source for understanding these disorders.

Nanoparticles With Affinity for α-Synuclein Sequester α-Synuclein to Form Toxic Aggregates in Neurons With Endolysosomal Impairment

“…In these cells, increased sphingosine levels due to GBA1 deletion or GCase deficiency impair endolysosomal integrity ( Figures 6 , 7 ). It is worth noting that GCase deficiency is associated with the accumulation of multiple lipid metabolites ( Abed Rabbo et al, 2021 ), and sphingosine may not be the only critical factor in this process.…”

Lysosomal positioning diseases: beyond substrate storage

“…In LSDs, primary substrate accumulation triggers a cascade of events leading to the accumulation of either cytosolic or luminal secondary substrates which generates defects in lysosomal reformation and the autophagic flux due to the impairment of the autophagosome–lysosome fusion [ 20 , 173 , 202 , 203 ]. Indeed, modifications of the lysosomal-autophagy mechanisms have been ascertained in many other LSDs [ 164 ], including Pompe disease [ 179 ], sphingolipidoses such as Gaucher disease [ 204 ], Fabry disease [ 205 , 206 ], and NPC [ 207 , 208 ], mucolipidosis II [ 135 ] and IV subtypes [ 209 ], Danon disease [ 126 ], and some NCLs [ 164 , 210 ]. In Anderson–Fabry disease, the accumulation of sphingolipid substrates in lysosomes inhibits autophagosome–lysosome fusion and disrupts the mTOR activation/inactivation cycle, interfering with the mTOR-mediated control of mitochondrial metabolism [ 129 ].…”

Lipid Metabolism Influence on Neurodegenerative Disease Progression: Is the Vehicle as Important as the Cargo?

“…This is likely due to the deacylation of glucosylceramide by lysosomal acid ceramidase, resulting in glucosylsphingosine, which also accumulates in Gaucher’s disease (Ferraz et al, 2016 ). Glucosylsphingosine can exit the lysosome, where it can be hydrolyzed by non-lysosomal GBA2 into ceramide, sphingosine, and sphingosine-1-phosphate (Abed Rabbo et al, 2021 ), resulting in complex alterations of downstream lipids that remain poorly understood.…”