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 Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

2016 ◽  
Vol 117 (2) ◽  
pp. 66-83 ◽  
Author(s):  
Priya S. Kishnani ◽  
Patricia I. Dickson ◽  
Laurie Muldowney ◽  
Jessica J. Lee ◽  
Amy Rosenberg ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Tolerance ◽  
Tolerance Induction ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Immune Tolerance Induction ◽  
Storage Diseases ◽  
Enzyme Replacement

The Emerging Role of the Pediatric Physical Therapist in Evaluation and Intervention for Individuals with Lysosomal Storage Diseases

2005 ◽  
Vol 17 (2) ◽  
pp. 128-139 ◽  
Author(s):  
Stephen M. Haley ◽  
Maria Fragala-Pinkham ◽  
Nancy K. Latham ◽  
Alison M. Skrinar ◽  
Deborah Cogswell
Keyword(s):  
Physical Therapist ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Storage 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 Ferroptosis and Its Modulation by Autophagy in Light of the Pathogenesis of Lysosomal Storage Diseases

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 365
Author(s):  
Karolina Pierzynowska ◽  
Estera Rintz ◽  
Lidia Gaffke ◽  
Grzegorz Węgrzyn
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Lysosomal Storage Diseases ◽  
Review Article ◽  
Lysosomal Storage ◽  
Ferrous Ions ◽  
Autophagy Flux ◽  
Considerable Contribution ◽  
Storage Diseases

Ferroptosis is one of the recently described types of cell death which is dependent on many factors, including the accumulation of iron and lipid peroxidation. Its induction requires various signaling pathways. Recent discovery of ferroptosis induction pathways stimulated by autophagy, so called autophagy-dependent ferroptosis, put our attention on the role of ferroptosis in lysosomal storage diseases (LSD). Lysosome dysfunction, observed in these diseases, may influence ferroptosis efficiency, with as yet unknown consequences for the function of cells, tissues, and organisms, due to the effects of ferroptosis on physiological and pathological metabolic processes. Modulation of levels of ferrous ions and enhanced oxidative stress, which are primary markers of ferroptosis, are often described as processes associated with the pathology of LSD. Inhibition of autophagy flux and resultant accumulation of autophagosomes in neuronopathic LSD may induce autophagy-dependent ferroptosis, indicating a considerable contribution of this process in neurodegeneration. In this review article, we describe molecular mechanisms of ferroptosis in light of LSD, underlining the modulation of levels of ferroptosis markers in these diseases. Furthermore, we propose a hypothesis about the possible involvement of autophagy-dependent ferroptosis in these disorders.

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 The role of automated analyzers in detecting abnormal granulation of leucocytes in lysosomal storage diseases: Maroteaux-Lamy disease

2013 ◽  
Vol 88 (6) ◽  
pp. 527-527 ◽  
Author(s):  
Elisa Piva ◽  
Michela Pelloso ◽  
Daniela Ciubotaru ◽  
Laura Penello ◽  
Alberto Burlina ◽  
...  
Keyword(s):  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Storage Diseases
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