Lyso-glycosphingolipids: presence and consequences

Eijk, Marco van; Ferraz, Maria J.; Boot, Rolf G.; Aerts, Johannes M. F. G.

doi:10.1042/ebc20190090

Cited by 43 publications

(33 citation statements)

References 103 publications

(139 reference statements)

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“…Fibrosis, inflammation and oxidative stress seem to play key roles in pathogenesis [ 47 , 48 , 49 , 50 ]. It has been hypothesized that lysoGb3 may also act as a pathogenic factor in FD [ 25 , 51 ]. A significant correlation of lysoGb3 lifetime exposure with overall disease severity was noted for classic male and female FD patients [ 41 ].…”

Section: Pathophysiologymentioning

confidence: 99%

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

et al. 2021

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Fabry disease (FD) is a lysosomal storage disorder (LSD) characterized by the deficiency of α-galactosidase A (α-GalA) and the consequent accumulation of toxic metabolites such as globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3). Early diagnosis and appropriate timely treatment of FD patients are crucial to prevent tissue damage and organ failure which no treatment can reverse. LSDs might profit from four main therapeutic strategies, but hitherto there is no cure. Among the therapeutic possibilities are intravenous administered enzyme replacement therapy (ERT), oral pharmacological chaperone therapy (PCT) or enzyme stabilizers, substrate reduction therapy (SRT) and the more recent gene/RNA therapy. Unfortunately, FD patients can only benefit from ERT and, since 2016, PCT, both always combined with supportive adjunctive and preventive therapies to clinically manage FD-related chronic renal, cardiac and neurological complications. Gene therapy for FD is currently studied and further strategies such as substrate reduction therapy (SRT) and novel PCTs are under investigation. In this review, we discuss the molecular basis of FD, the pathophysiology and diagnostic procedures, together with the current treatments and potential therapeutic avenues that FD patients could benefit from in the future.

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Section: Pathophysiologymentioning

confidence: 99%

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

et al. 2021

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“…Among the enzymes tested, only FAAH increased the release of fatty acid from sulfatide. ASAH1 has been implicated in the deacylation of the GSLs glucosylceramide, galactosylceramide, and globotriaosylceramide to their corresponding lyso-forms ( 8 ). It is, therefore, important to point out that no deacylation of sulfatide was detectable after transient or stable overexpression of ASAH1.…”

Section: Discussionmentioning

confidence: 99%

“…The origin of lyso-GSLs has been debated for a long time. Recent genetic and pharmacological data suggest that ASAH1 has a broader substrate specificity than initially supposed and deacylates not only ceramide, but also certain GSLs ( 8 ). For sulfatide, however, cleavage by ASAH1 could not be demonstrated so far.…”

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confidence: 99%

Deletion of fatty acid amide hydrolase reduces lyso-sulfatide levels but exacerbates metachromatic leukodystrophy in mice

Yaghootfam

Gehrig

Sylvester

et al. 2021

Journal of Biological Chemistry

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An inherited deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy (MLD) characterized by massive intralysosomal storage of the acidic glycosphingolipid sulfatide and progressive demyelination. Lyso-sulfatide, which differs from sulfatide by the lack of the N-linked fatty acid, also accumulates in MLD and is considered a key driver of pathology although its concentrations are far below sulfatide levels. However, the metabolic origin of lyso-sulfatide is unknown. We show here that ASA-deficient murine macrophages and microglial cells express an endo-N-deacylase that cleaves the N-linked fatty acid from sulfatide. An ASA-deficient astrocytoma cell line devoid of this activity was used to identify the enzyme by overexpressing 13 deacylases with potentially matching substrate specificities. Hydrolysis of sulfatide was detected only in cells overexpressing the enzyme fatty acid amide hydrolase (FAAH). A cell-free assay with recombinant FAAH confirmed the novel role of this enzyme in sulfatide hydrolysis. Consistent with the in vitro data, deletion of FAAH lowered lyso-sulfatide levels in a mouse model of MLD. Regardless of the established cytotoxicity of lyso-sulfatide and the anti-inflammatory effects of FAAH inhibition seen in mouse models of several neurological diseases, genetic inactivation of FAAH did not mitigate, but rather exacerbated the disease phenotype of MLD mice. This unexpected finding was reflected by worsening of rotarod performance, increase of anxiety-related exploratory activity, aggravation of peripheral neuropathy, and reduced life expectancy. Thus, we conclude that FAAH has a protective function in MLD and may represent a novel therapeutic target for treatment of this fatal condition.

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“…The key sphingolipid that serves as a building block for all complex (glyco)sphingolipids (GSL) is ceramide and a simplified scheme is depicted in Figure 3 . The formation of glycosylated ceramide species including galactosylceramide and its derivative sulfatide and glucosylceramide is included [ 22 , 23 ]. The degradation of GSL occurs within the lysosome by the stepwise removal of carbohydrate moieties.…”

Section: The Catabolic Defective Storage Macrophagesmentioning

confidence: 99%

The Unique Phenotype of Lipid-Laden Macrophages

Eijk

Aerts

2021

IJMS

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Macrophages are key multi-talented cells of the innate immune system and are equipped with receptors involved in damage and pathogen recognition with connected immune response guiding signaling systems. In addition, macrophages have various systems that are involved in the uptake of extracellular and intracellular cargo. The lysosomes in macrophages play a central role in the digestion of all sorts of macromolecules and the entry of nutrients to the cytosol, and, thus, the regulation of endocytic processes and autophagy. Simplistically viewed, two macrophage phenotype extremes exist. On one end of the spectrum, the classically activated pro-inflammatory M1 cells are present, and, on the other end, alternatively activated anti-inflammatory M2 cells. A unique macrophage population arises when lipid accumulation occurs, either caused by flaws in the catabolic machinery, which is observed in lysosomal storage disorders, or as a result of an acquired condition, which is found in multiple sclerosis, obesity, and cardiovascular disease. The accompanying overload causes a unique metabolic activation phenotype, which is discussed here, and, consequently, a unifying phenotype is proposed.

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Lyso-glycosphingolipids: presence and consequences

Cited by 43 publications

References 103 publications

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Fabry Disease: Molecular Basis, Pathophysiology, Diagnostics and Potential Therapeutic Directions

Deletion of fatty acid amide hydrolase reduces lyso-sulfatide levels but exacerbates metachromatic leukodystrophy in mice

The Unique Phenotype of Lipid-Laden Macrophages

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