scholarly journals Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Fernanda Cabrera-Reyes ◽  
Claudia Parra-Ruiz ◽  
María Isabel Yuseff ◽  
Silvana Zanlungo
Keyword(s):  
B Cells ◽  
Lysosomal Storage Diseases ◽  
Cellular Level ◽  
Lysosomal Storage ◽  
Cellular Mechanisms ◽  
Membrane Contact Sites ◽  
Metabolic Functions ◽  
Metabolic Imbalance ◽  
Niemann Pick ◽  
Metabolic Dysfunctions

Lipid-related disorders, which primarily affect metabolic tissues, including adipose tissue and the liver are associated with alterations in lysosome homeostasis. Obesity is one of the more prevalent diseases, which results in energy imbalance within metabolic tissues and lysosome dysfunction. Less frequent diseases include Niemann-Pick type C (NPC) and Gaucher diseases, both of which are known as Lysosomal Storage Diseases (LSDs), where lysosomal dysfunction within metabolic tissues remains to be fully characterized. Adipocytes and hepatocytes share common pathways involved in the lysosome-autophagic axis, which are regulated by the function of cathepsins and CD36, an immuno-metabolic receptor and display alterations in lipid diseases, and thereby impacting metabolic functions. In addition to intrinsic defects observed in metabolic tissues, cells of the immune system, such as B cells can infiltrate adipose and liver tissues, during metabolic imbalance favoring inflammation. Moreover, B cells rely on lysosomes to promote the processing and presentation of extracellular antigens and thus could also present lysosome dysfunction, consequently affecting such functions. On the other hand, growing evidence suggests that cells accumulating lipids display defective inter-organelle membrane contact sites (MCSs) established by lysosomes and other compartments, which contribute to metabolic dysfunctions at the cellular level. Overall, in this review we will discuss recent findings addressing common mechanisms that are involved in lysosome dysregulation in adipocytes and hepatocytes during obesity, NPC, and Gaucher diseases. We will discuss whether these mechanisms may modulate the function of B cells and how inter-organelle contacts, emerging as relevant cellular mechanisms in the control of lipid homeostasis, have an impact on these diseases.

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 Elevated Dipeptidyl Peptidase IV (DPP-IV) Activity in Plasma from Patients with Various Lysosomal Diseases

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 320
Author(s):  
Agnieszka Ługowska ◽  
Galina Baydakova ◽  
Alex Ilyushkina ◽  
Ekaterina Zakharova ◽  
Hanna Mierzewska ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Basic Research ◽  
Lysosomal Storage Diseases ◽  
Dipeptidyl Peptidase ◽  
Dipeptidyl Peptidase Iv ◽  
Lysosomal Storage ◽  
Dpp Iv ◽  
Niemann Pick Disease ◽  
Multiple Processes ◽  
Niemann Pick

Increased activity of dipeptidyl peptidase IV (DPP-IV) was reported earlier in patients with different types of mucopolysaccharidoses. DPP-IV (also known as CD26 lymphocyte T surface antigen) is a transmembrane protein showing protease activity. This enzyme displays various functions in the organism and plays an important role in multiple processes like glucose metabolism, nociception, cell-adhesion, psychoneuroendocrine regulation, immune response and cardiovascular adaptation. In order to evaluate DPP-IV in lysosomal storage diseases (LSD), we examined its activity in plasma samples from 307 patients affected with 24 different LSDs and in 75 control persons. Our results revealed elevated DPP-IV activity especially in individuals affected with mucolipidosis II/III, alpha-mannosidosis, and mucopolysaccharidoses types III, II, and I (p < 0.05). In other LSDs the DPP-IV activity was still significantly increased, but to a lesser extent. In patients with Gaucher disease, ceroid lipofuscinosis type 1 (CLN1), Niemann–Pick disease type C and A, Krabbe and Pompe diseases, gangliosidosis GM2 and metachromatic leukodystrophy discreet or no changes in DPP-IV activity were observed. DPP-IV may serve as a first-tier diagnostic procedure or additional biochemical analysis in recognizing patients with some LSDs. DPP-IV may become an object of basic research for a better understanding of LSDs.

scholarly journals Lyso-glycosphingolipids: presence and consequences

2020 ◽  
Vol 64 (3) ◽  
pp. 565-578 ◽  
Author(s):  
Marco van Eijk ◽  
Maria J. Ferraz ◽  
Rolf G. Boot ◽  
Johannes M.F.G. Aerts
Keyword(s):  
Metachromatic Leukodystrophy ◽  
Lysosomal Storage Diseases ◽  
Krabbe Disease ◽  
Lysosomal Storage ◽  
Gm2 Gangliosidosis ◽  
Acid Ceramidase ◽  
Lysosomal Diseases ◽  
Type C ◽  
Niemann Pick ◽  
Storage Disorders

Abstract Lyso-glycosphingolipids are generated in excess in glycosphingolipid storage disorders. In the course of these pathologies glycosylated sphingolipid species accumulate within lysosomes due to flaws in the respective lipid degrading machinery. Deacylation of accumulating glycosphingolipids drives the formation of lyso-glycosphingolipids. In lysosomal storage diseases such as Gaucher Disease, Fabry Disease, Krabbe disease, GM1 -and GM2 gangliosidosis, Niemann Pick type C and Metachromatic leukodystrophy massive intra-lysosomal glycosphingolipid accumulation occurs. The lysosomal enzyme acid ceramidase generates the deacylated lyso-glycosphingolipid species. This review discusses how the various lyso-glycosphingolipids are synthesized, how they may contribute to abnormal immunity in glycosphingolipid storing lysosomal diseases and what therapeutic opportunities exist.

scholarly journals Gaucher disease and other storage disorders

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 13-18 ◽  
Author(s):  
Gregory A. Grabowski
Keyword(s):  
Gaucher Disease ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Intracellular Enzyme ◽  
Nonalcoholic Fatty Liver ◽  
Common Diseases ◽  
Age Related ◽  
Niemann Pick ◽  
Apoptotic Pathways ◽  
The Impact

Abstract In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a “primary epithelioma of the spleen.” The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.

scholarly journals Lysosomal Dysfunction Results in Altered Energy Balance

2007 ◽  
Vol 282 (49) ◽  
pp. 35765-35771 ◽  
Author(s):  
Josh C. Woloszynek ◽  
Trey Coleman ◽  
Clay F. Semenkovich ◽  
Mark S. Sands
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Caloric Intake ◽  
Lysosomal Storage Diseases ◽  
Lipid Absorption ◽  
Unknown Etiology ◽  
Caloric Content ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Caloric Density ◽  
Niemann Pick

The mucopolysaccharidosis (MPS) type VII mouse was originally described as the adipose storage deficiency mouse because of its extreme lean phenotype of unknown etiology. Here, we show that adipose storage deficiency and lower leptin levels are common to five different lysosomal storage diseases (LSDs): MPSI, MPSIIIB, MPSVII, Niemann-Pick type A/B, and infantile neuronal ceroid lipofuscinosis. Elevated circulating pro-inflammatory proteins (VCAM1 and MCP1) were found in multiple LSDs. Multiple anti-inflammatory strategies (dexamethasone, MCP1 deficiency, M3 expression) failed to alter adiposity in LSD animals. All of the models had normal or greater caloric intake and lower to normal metabolic rate, fasting plasma glucose, non-esterified fatty acids, cholesterol, and triglycerides. Triglycerides were lower in the livers of MPSI mice, and the trend was lower in the muscle. Lipid absorption and processing in MPSI mice were indistinguishable from those in normal mice following oral gavage of olive oil. The increased lean mass of MPSI and MPSIIIB mice suggests a shift in adipose triglycerides to lysosomal storage. In agreement, MPSI livers had a similar total caloric content but reduced caloric density, indicating a shift in energy from lipids to proteins/carbohydrates (lysosomal storage). Enzyme replacement therapy normalized the caloric density within 48 h without reducing total caloric content. This was due to an increase in lipids. Recycling of stored material is likely reduced or nonexistent. Therefore, to maintain homeostasis, energy is likely diverted to synthesis at the expense of typical energy storage depots. Thus, these diseases will serve as important tools in studying the role of lysosome function in metabolism and obesity.

scholarly journals Mechanism of Secondary Ganglioside and Lipid Accumulation in Lysosomal Disease

2020 ◽  
Vol 21 (7) ◽  
pp. 2566 ◽  
Author(s):  
Bernadette Breiden ◽  
Konrad Sandhoff
Keyword(s):  
Chondroitin Sulfate ◽  
Lipid Accumulation ◽  
Lysosomal Storage Diseases ◽  
Disease Type ◽  
Lysosomal Storage ◽  
Lysosomal Disease ◽  
Activator Protein ◽  
Niemann Pick Disease ◽  
Niemann Pick ◽  
Pick Disease

Gangliosidoses are caused by monogenic defects of a specific hydrolase or an ancillary sphingolipid activator protein essential for a specific step in the catabolism of gangliosides. Such defects in lysosomal function cause a primary accumulation of multiple undegradable gangliosides and glycosphingolipids. In reality, however, predominantly small gangliosides also accumulate in many lysosomal diseases as secondary storage material without any known defect in their catabolic pathway. In recent reconstitution experiments, we identified primary storage materials like sphingomyelin, cholesterol, lysosphingolipids, and chondroitin sulfate as strong inhibitors of sphingolipid activator proteins (like GM2 activator protein, saposin A and B), essential for the catabolism of many gangliosides and glycosphingolipids, as well as inhibitors of specific catabolic steps in lysosomal ganglioside catabolism and cholesterol turnover. In particular, they trigger a secondary accumulation of ganglioside GM2, glucosylceramide and cholesterol in Niemann–Pick disease type A and B, and of GM2 and glucosylceramide in Niemann–Pick disease type C. Chondroitin sulfate effectively inhibits GM2 catabolism in mucopolysaccharidoses like Hurler, Hunter, Sanfilippo, and Sly syndrome and causes a secondary neuronal ganglioside GM2 accumulation, triggering neurodegeneration. Secondary ganglioside and lipid accumulation is furthermore known in many more lysosomal storage diseases, so far without known molecular basis.

scholarly journals Murine Models of Lysosomal Storage Diseases Exhibit Differences in Brain Protein Aggregation and Neuroinflammation

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 446
Author(s):  
Jennifer Clarke ◽  
Can Kayatekin ◽  
Catherine Viel ◽  
Lamya Shihabuddin ◽  
Sergio Pablo Sardi
Keyword(s):  
Protein Aggregation ◽  
Mouse Models ◽  
Microglial Activation ◽  
Lysosomal Storage Diseases ◽  
Specific Protein ◽  
Therapeutic Interventions ◽  
Proteinase K ◽  
Lysosomal Storage ◽  
Storage Diseases ◽  
Niemann Pick

Genetic, epidemiological and experimental evidence implicate lysosomal dysfunction in Parkinson’s disease (PD) and related synucleinopathies. Investigate several mouse models of lysosomal storage diseases (LSDs) and evaluate pathologies reminiscent of synucleinopathies. We obtained brain tissue from symptomatic mouse models of Gaucher, Fabry, Sandhoff, Niemann–Pick A (NPA), Hurler, Pompe and Niemann–Pick C (NPC) diseases and assessed for the presence of Lewy body-like pathology (proteinase K-resistant α-synuclein and tau aggregates) and neuroinflammation (microglial Iba1 and astrocytic GFAP) by immunofluorescence. All seven LSD models exhibited evidence of proteinopathy and/or inflammation in the central nervous system (CNS). However, these phenotypes were divergent. Gaucher and Fabry mouse models displayed proteinase K-resistant α-synuclein and tau aggregates but no neuroinflammation; whereas Sandhoff, NPA and NPC showed marked neuroinflammation and no overt proteinopathy. Pompe disease animals uniquely displayed widespread distribution of tau aggregates accompanied by moderate microglial activation. Hurler mice also demonstrated proteinopathy and microglial activation. The present study demonstrated additional links between LSDs and pathogenic phenotypes that are hallmarks of synucleinopathies. The data suggest that lysosomal dysregulation can contribute to brain region-specific protein aggregation and induce widespread neuroinflammation in the brain. However, only a few LSD models examined exhibited phenotypes consistent with synucleinopathies. While no model can recapitulate the complexity of PD, they can enable the study of specific pathways and mechanisms contributing to disease pathophysiology. The present study provides evidence that there are existing, previously unutilized mouse models that can be employed to study pathogenic mechanisms and gain insights into potential PD subtypes, helping to determine if they are amenable to pathway-specific therapeutic interventions.

scholarly journals A Phenotypic Compound Screening Assay for Lysosomal Storage Diseases

2013 ◽  
Vol 19 (1) ◽  
pp. 168-175 ◽  
Author(s):  
Miao Xu ◽  
Ke Liu ◽  
Manju Swaroop ◽  
Wei Sun ◽  
Seameen J. Dehdashti ◽  
...  
Keyword(s):  
Drug Development ◽  
Lysosomal Storage Diseases ◽  
Lysosomal Storage ◽  
Screening Assay ◽  
Primary Fibroblast ◽  
Storage Diseases ◽  
Lead Compounds ◽  
Compound Screening ◽  
Niemann Pick ◽  
Microscopic Measurement

The lysosome is a vital cellular organelle that primarily functions as a recycling center for breaking down unwanted macromolecules through a series of hydrolases. Functional deficiencies in lysosomal proteins due to genetic mutations have been found in more than 50 lysosomal storage diseases that exhibit characteristic lipid/macromolecule accumulation and enlarged lysosomes. Recently, the lysosome has emerged as a new therapeutic target for drug development for the treatment of lysosomal storage diseases. However, a suitable assay for compound screening against the diseased lysosomes is currently unavailable. We have developed a Lysotracker staining assay that measures the enlarged lysosomes in patient-derived cells using both fluorescence intensity readout and fluorescence microscopic measurement. This phenotypic assay has been tested in patient cells obtained from several lysosomal storage diseases and validated using a known compound, methyl-β-cyclodextrin, in primary fibroblast cells derived from Niemann Pick C disease patients. The results demonstrate that the Lysotracker assay can be used in compound screening for the identification of lead compounds that are capable of reducing enlarged lysosomes for drug development.

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