scholarly journals WASH is required for lysosomal recycling and efficient autophagic and phagocytic digestion

2013 ◽  
Vol 24 (17) ◽  
pp. 2714-2726 ◽  
Author(s):  
Jason S. King ◽  
Aurélie Gueho ◽  
Monica Hagedorn ◽  
Navin Gopaldass ◽  
Florence Leuba ◽  
...  
Keyword(s):  
Cathepsin D ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Endosomal Sorting ◽  
Lipid Catabolism ◽  
Multilamellar Bodies ◽  
Important Regulator ◽  
Intracellular Vesicles ◽  
Syndrome Protein

Wiskott-Aldrich syndrome protein and SCAR homologue (WASH) is an important regulator of vesicle trafficking. By generating actin on the surface of intracellular vesicles, WASH is able to directly regulate endosomal sorting and maturation. We report that, in Dictyostelium, WASH is also required for the lysosomal digestion of both phagocytic and autophagic cargo. Consequently, Dictyostelium cells lacking WASH are unable to grow on many bacteria or to digest their own cytoplasm to survive starvation. WASH is required for efficient phagosomal proteolysis, and proteomic analysis demonstrates that this is due to reduced delivery of lysosomal hydrolases. Both protease and lipase delivery are disrupted, and lipid catabolism is also perturbed. Starvation-induced autophagy therefore leads to phospholipid accumulation within WASH-null lysosomes. This causes the formation of multilamellar bodies typical of many lysosomal storage diseases. Mechanistically, we show that, in cells lacking WASH, cathepsin D becomes trapped in a late endosomal compartment, unable to be recycled to nascent phagosomes and autophagosomes. WASH is therefore required for the maturation of lysosomes to a stage at which hydrolases can be retrieved and reused.

Innate immune responses in the brain of sphingolipid lysosomal storage diseases

2015 ◽  
Vol 396 (6-7) ◽  
pp. 659-667 ◽  
Author(s):  
Einat B. Vitner ◽  
Anthony H. Futerman ◽  
Nick Platt
Keyword(s):  
Lysosomal Storage Diseases ◽  
Sandhoff Disease ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Storage Diseases ◽  
Niemann Pick ◽  
The Brain

Abstract Lysosomal storage diseases (LSDs) are mainly caused by the defective activity of lysosomal hydrolases. A sub-class of LSDs are the sphingolipidoses, in which sphingolipids accumulate intra-cellularly. We here discuss the role of innate immunity in the sphingolipidoses, and compare the pathways of activation in two classical sphingolipidoses, namely Gaucher disease and Sandhoff disease, and in Niemann-Pick C disease, in which the main storage material is cholesterol but sphingolipids also accumulate. We discuss the mechanisms leading to neuroinflammation, and the different pathways of neuroinflammation in the different diseases, and suggest that intervention in these pathways may be a useful therapeutic approach to address these devastating human diseases.

scholarly journals Cell-autonomous expression of the acid hydrolase galactocerebrosidase

2020 ◽  
Vol 117 (16) ◽  
pp. 9032-9041
Author(s):  
Christina R. Mikulka ◽  
Joshua T. Dearborn ◽  
Bruno A. Benitez ◽  
Amy Strickland ◽  
Lin Liu ◽  
...  
Keyword(s):  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Krabbe Disease ◽  
Specific Cell ◽  
Acid Hydrolase ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Soluble Acid ◽  
Enzyme Deficient

Lysosomal storage diseases (LSDs) are typically caused by a deficiency in a soluble acid hydrolase and are characterized by the accumulation of undegraded substrates in the lysosome. Determining the role of specific cell types in the pathogenesis of LSDs is a major challenge due to the secretion and subsequent uptake of lysosomal hydrolases by adjacent cells, often referred to as “cross-correction.” Here we create and validate a conditional mouse model for cell-autonomous expression of galactocerebrosidase (GALC), the lysosomal enzyme deficient in Krabbe disease. We show that lysosomal membrane-tethered GALC (GALCLAMP1) retains enzyme activity, is able to cleave galactosylsphingosine, and is unable to cross-correct. Ubiquitous expression of GALCLAMP1 fully rescues the phenotype of the GALC-deficient mouse (Twitcher), and widespread deletion of GALCLAMP1 recapitulates the Twitcher phenotype. We demonstrate the utility of this model by deleting GALCLAMP1 specifically in myelinating Schwann cells in order to characterize the peripheral neuropathy seen in Krabbe disease.

scholarly journals The Link between Gaucher Disease and Parkinson’s Disease Sheds Light on Old and Novel Disorders of Sphingolipid Metabolism

2019 ◽  
Vol 20 (13) ◽  
pp. 3304 ◽  
Author(s):  
Rossella Indellicato ◽  
Marco Trinchera
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gaucher Disease ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Sphingolipid Metabolism ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Inborn Errors ◽  
Vesicle Traffic

Sphingolipid metabolism starts with the biosynthesis of ceramide, a bioactive lipid and the backbone for the biosynthesis of complex sphingolipids such as sphingomyelin and glycosphingolipids. These are degraded back to ceramide and then to sphingosine, which enters the ceramide–sphingosine-1-phosphate signaling pathway or is further degraded. Several enzymes with multiple catalytic properties and subcellular localizations are thus involved in such metabolism. Hereditary defects of lysosomal hydrolases have been known for several years to be the cause of lysosomal storage diseases such as gangliosidoses, Gaucher disease, Niemann–Pick disease, Krabbe disease, Fabry disease, and Farber disease. More recently, many other inborn errors of sphingolipid metabolism have been recognized, involving enzymes responsible for the biosynthesis of ceramide, sphingomyelin, and glycosphingolipids. Concurrently, epidemiologic and biochemical evidence has established a link between Gaucher disease and Parkinson’s disease, showing that glucocerebrosidase variants predispose individuals to α-synuclein accumulation and neurodegeneration even in the heterozygous status. This appears to be due not only to lysosomal overload of non-degraded glucosylceramide, but to the derangement of vesicle traffic and autophagy, including mitochondrial autophagy, triggered by both sphingolipid intermediates and misfolded proteins. In this review, old and novel disorders of sphingolipid metabolism, in particular those of ganglioside biosynthesis, are evaluated in light of recent investigations of the link between Gaucher disease and Parkinson’s disease, with the aim of better understanding their pathogenic mechanisms and addressing new potential therapeutic strategies.

Lysosomal Glycosphingolipid Storage Diseases

2019 ◽  
Vol 88 (1) ◽  
pp. 461-485 ◽  
Author(s):  
Bernadette Breiden ◽  
Konrad Sandhoff
Keyword(s):  
Plasma Membranes ◽  
Secretory Pathway ◽  
Lysosomal Storage Diseases ◽  
Lipid Binding ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Hydrophobic Membrane ◽  
Storage Diseases ◽  
Storage Compounds ◽  
Outer Leaflet

Glycosphingolipids are cell-type-specific components of the outer leaflet of mammalian plasma membranes. Gangliosides, sialic acid–containing glycosphingolipids, are especially enriched on neuronal surfaces. As amphi-philic molecules, they comprise a hydrophilic oligosaccharide chain attached to a hydrophobic membrane anchor, ceramide. Whereas glycosphingolipid formation is catalyzed by membrane-bound enzymes along the secretory pathway, degradation takes place at the surface of intralysosomal vesicles of late endosomes and lysosomes catalyzed in a stepwise fashion by soluble hydrolases and assisted by small lipid-binding glycoproteins. Inherited defects of lysosomal hydrolases or lipid-binding proteins cause the accumulation of undegradable material in lysosomal storage diseases (GM1 and GM2 gangliosidosis; Fabry, Gaucher, and Krabbe diseases; and metachromatic leukodystrophy). The catabolic processes are strongly modified by the lipid composition of the substrate-carrying membranes, and the pathological accumulation of primary storage compounds can trigger an accumulation of secondary storage compounds (e.g., small glycosphingolipids and cholesterol in Niemann-Pick disease).

scholarly journals Fisiologie en patofísiologie van selorganelle

1997 ◽  
Vol 16 (2) ◽  
pp. 56-64
Author(s):  
J. J. Theron ◽  
N. Claasen ◽  
A. Panzer
Keyword(s):  
Chemical Nature ◽  
Lysosomal Storage Diseases ◽  
Congenital Absence ◽  
Specific Substrate ◽  
Lysosomal Storage ◽  
Lysosomal Hydrolases ◽  
Storage Diseases ◽  
Clinical Syndromes ◽  
Different Types ◽  
Hydrolysis Of

Congenital absence of one or more lysosomal hydrolases results in accumulation of the relevant substrate and development of the so- called lysosomal storage diseases (LSD). Approximately 22 different types of LSD are known, which are divided into three groups according to the chemical nature of the specific substrate: sphingolipidoses, mucopolvsaccharridoses (defective hydrolysis of glycosaminoglycans) and glycoproteinoses. Other lysosomal clinical syndromes may result from defects in the biogenesis of the organelle or abnormalities in transport of metabolites across the lysosomal membrane.

Electron Microscopy in the diagnosis of lysosomal storage diseases

1989 ◽  
Vol 47 ◽  
pp. 866-867
Author(s):  
Carole Vogler ◽  
Harvey S. Rosenberg
Keyword(s):  
Electron Microscopy ◽  
Lysosomal Enzyme ◽  
Rectal Mucosa ◽  
Lysosomal Storage Diseases ◽  
Cell Types ◽  
Lysosomal Storage ◽  
Storage Material ◽  
Ultrastructural Examination ◽  
Blood Leukocytes ◽  
Storage Diseases

Diagnostic procedures for evaluation of patients with lysosomal storage diseases (LSD) seek to identify a deficiency of a responsible lysosomal enzyme or accumulation of a substance that requires the missing enzyme for degradation. Most patients with LSD have progressive neurological degeneration and may have a variety of musculoskeletal and visceral abnormalities. In the LSD, the abnormally diminished lysosomal enzyme results in accumulation of unmetabolized catabolites in distended lysosomes. Because of the subcellular morphology and size of lysosomes, electron microscopy is an ideal tool to study tissue from patients with suspected LSD. In patients with LSD all cells lack the specific lysosomal enzyme but the distribution of storage material is dependent on the extent of catabolism of the substrate in each cell type under normal circumstances. Lysosmal storages diseases affect many cell types and tissues. Storage material though does not accumulate in all tissues and cell types and may be different biochemically and morphologically in different tissues.Conjunctiva, skin, rectal mucosa and peripheral blood leukocytes may show ultrastructural evidence of lysosomal storage even in the absence of clinical findings and thus any of these tissues can be used for ultrastructural examination in the diagnostic evaluation of patients with suspected LSD. Biopsy of skin and conjunctiva are easily obtained and provide multiple cell types including endothelium, epithelium, fibroblasts and nerves for ultrastructural study. Fibroblasts from skin and conjunctiva can also be utilized for the initiation of tissue cultures for chemical assays. Brain biopsy has been largely replaced by biopsy of more readily obtained tissue and by biochemical assays. Such assays though may give equivical or nondiagnostic results and in some lysosomal storage diseases an enzyme defect has not yet been identified and diagnoses can be made only by ultrastructural examination.

scholarly journals Sphingolipid lysosomal storage diseases: from bench to bedside

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Muna Abed Rabbo ◽  
Yara Khodour ◽  
Laurie S. Kaguni ◽  
Johnny Stiban
Keyword(s):  
Basic Research ◽  
Lysosomal Storage Diseases ◽  
Therapeutic Strategies ◽  
Clinical Applications ◽  
Late Nineteenth Century ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
The Past ◽  
Health And Disease ◽  
General Aspects

AbstractJohann 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.

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