scholarly journals Glycoprotein Non-Metastatic Protein B: An Emerging Biomarker for Lysosomal Dysfunction in Macrophages

2018 ◽  
Vol 20 (1) ◽  
pp. 66 ◽  
Author(s):  
Martijn van der Lienden ◽  
Paulo Gaspar ◽  
Rolf Boot ◽  
Johannes Aerts ◽  
Marco van Eijk
Keyword(s):  
Gaucher Disease ◽  
Enzymatic Degradation ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Substrate Reduction ◽  
Lysosomal Dysfunction ◽  
Enzyme Supplementation ◽  
Storage Cells ◽  
Storage Disorders ◽  
Protein B

Several diseases are caused by inherited defects in lysosomes, the so-called lysosomal storage disorders (LSDs). In some of these LSDs, tissue macrophages transform into prominent storage cells, as is the case in Gaucher disease. Here, macrophages become the characteristic Gaucher cells filled with lysosomes laden with glucosylceramide, because of their impaired enzymatic degradation. Biomarkers of Gaucher cells were actively searched, particularly after the development of costly therapies based on enzyme supplementation and substrate reduction. Proteins selectively expressed by storage macrophages and secreted into the circulation were identified, among which glycoprotein non-metastatic protein B (GPNMB). This review focusses on the emerging potential of GPNMB as a biomarker of stressed macrophages in LSDs as well as in acquired pathologies accompanied by an excessive lysosomal substrate load in macrophages.

scholarly journals Small–molecule therapeutics for the treatment of glycolipid lysosomal storage disorders

2003 ◽  
Vol 358 (1433) ◽  
pp. 927-945 ◽  
Author(s):  
Terry D. Butters ◽  
Howard R. Mellor ◽  
Keishi Narita ◽  
Raymond A. Dwek ◽  
Frances M. Platt
Keyword(s):  
Catalytic Activity ◽  
Lysosomal Storage Disorders ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Substrate Reduction ◽  
Treatment Demand ◽  
Small Molecule Therapeutics ◽  
Storage Disorders

Glycosphingolipid (GSL) lysosomal storage disorders are a small but challenging group of human diseases to treat. Although these disorders appear to be monogenic in origin, where the catalytic activity of enzymes in GSL catabolism is impaired, the clinical presentation and severity of disease are heterogeneous. Present attitudes to treatment demand individual therapeutics designed to match the specific disease–related gene defect; this is an acceptable approach for those diseases with high frequency, but it lacks viability for extremely rare conditions. An alternative therapeutic approach termed ‘substrate deprivation’ or ‘substrate reduction therapy’ (SRT) aims to balance cellular GSL biosynthesis with the impairment in catalytic activity seen in lysosomal storage disorders. The development of N–alkylated iminosugars that have inhibitory activity against the first enzyme in the pathway for glucosylating sphingolipid in eukaryotic cells, ceramide–specific glucosyltransferase, offers a generic therapeutic for the treatment of all glucosphingolipidoses. The successful use of N–alkylated iminosugars to establish SRT as an alternative therapeutic strategy has been demonstrated in in vitro , in vivo and in clinical trials for type 1 Gaucher disease. The implications of these studies and the prospects of improvement to the design of iminosugar compounds for treating Gaucher and other GSL lysosomal storage disorders will be discussed.

Treatments for lysosomal storage disorders

2010 ◽  
Vol 38 (6) ◽  
pp. 1465-1468 ◽  
Author(s):  
Robin Lachmann
Keyword(s):  
Genetic Disorders ◽  
Lysosomal Storage Disorders ◽  
Substrate Reduction Therapy ◽  
Lysosomal Storage ◽  
Enzyme Replacement ◽  
Haemopoietic Stem Cell ◽  
Substrate Reduction ◽  
Haemopoietic Stem Cell Transplantation ◽  
Late Stages ◽  
Storage Disorders

There are over 70 human diseases that are caused by defects in various aspects of lysosomal function. Until 20 years ago, the only specific therapy available for lysosomal storage disorders was allogeneic haemopoietic stem cell transplantation. Over the last two decades, there has been remarkable progress and there are now licensed treatments for seven of these diseases. In some cases, a choice of agents is available. For selected enzyme-deficiency disordes, ERT (enzyme-replacement therapy) has proved to be highly effective. In other cases, ERT has been less impressive, and it seems that it is not possible to efficiently deliver recombinant enzyme to all tissues. These difficulties have led to the development of other small-molecule-based therapies, and a drug for SRT (substrate-reduction therapy) is now licensed and potential chaperone molecules for ERT are in the late stages of clinical development. Nonetheless, there is still significant unmet clinical need, particularly when it comes to treating LSDs which affect the brain. LSDs have led the way in the development of treatment for genetic disorders, and it seems likely that there will be further therapeutic innovations in the future.

scholarly journals Efficacy of pentosan polysulfate in in vitro models of lysosomal storage disorders: Fabry and Gaucher Disease

PLoS ONE ◽  
2019 ◽  
Vol 14 (5) ◽  
pp. e0217780 ◽  
Author(s):  
Andrea N. Crivaro ◽  
Juan M. Mucci ◽  
Constanza M. Bondar ◽  
Maximiliano E. Ormazabal ◽  
Romina Ceci ◽  
...  
Keyword(s):  
Gaucher Disease ◽  
In Vitro Models ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Pentosan Polysulfate ◽  
Storage Disorders

scholarly journals Fronto-temporal dementia risk gene TMEM106B has opposing effects in different lysosomal storage disorders

2020 ◽  
Author(s):  
Azucena Perez-Canamas ◽  
Hideyuki Takahashi ◽  
Jane A Lindborg ◽  
Stephen M Strittmatter
Keyword(s):  
Gaucher Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Vacuolar Atpase ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Compartment ◽  
Lysosomal Ph ◽  
Ceroid Lipofuscinosis ◽  
Storage Disorders

Abstract TMEM106B is a transmembrane protein localized to the endo-lysosomal compartment. Genome-wide association studies have identified TMEM106B as a risk modifier of Alzheimer’s disease and frontotemporal lobar degeneration, especially with progranulin haploinsufficiency. We recently demonstrated that TMEM106B loss rescues progranulin null mouse phenotypes including lysosomal enzyme dysregulation, neurodegeneration and behavioural alterations. However, the reason whether TMEM106B is involved in other neurodegenerative lysosomal diseases is unknown. Here, we evaluate the potential role of TMEM106B in modifying the progression of lysosomal storage disorders using progranulin-independent models of Gaucher disease and neuronal ceroid lipofuscinosis. To study Gaucher disease, we employ a pharmacological approach using the inhibitor conduritol B epoxide in wild-type and hypomorphic Tmem106b−/− mice. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities in the pharmacological model of Gaucher disease, similar to its effect on certain progranulin null phenotypes. In order to examine the role of TMEM106B in neuronal ceroid lipofuscinosis, we crossbred Tmem106b−/− mice with Ppt1−/−, a genetic model of the disease. In contrast to its conduritol B epoxide-rescuing effect, TMEM106B loss exacerbates Purkinje cell degeneration and motor deficits in Ppt1−/− mice. Mechanistically, TMEM106B is known to interact with subunits of the vacuolar ATPase and influence lysosomal acidification. In the pharmacological Gaucher disease model, the acidified lysosomal compartment is enhanced and TMEM106B loss rescues in vivo phenotypes. In contrast, gene-edited neuronal loss of Ppt1 causes a reduction in vacuolar ATPase levels and impairment of the acidified lysosomal compartment, and TMEM106B deletion exacerbates the mouse Ppt1−/− phenotype. Our findings indicate that TMEM106B differentially modulates the progression of the lysosomal storage disorders Gaucher disease and neuronal ceroid lipofuscinosis. The effect of TMEM106B in neurodegeneration varies depending on vacuolar ATPase state and modulation of lysosomal pH. These data suggest TMEM106B as a target for correcting lysosomal pH alterations, and in particular for therapeutic intervention in Gaucher disease and neuronal ceroid lipofuscinosis.

scholarly journals The Role of Exosomes in Lysosomal Storage Disorders

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 576
Author(s):  
Adenrele M. Gleason ◽  
Elizabeth G. Woo ◽  
Cindy McKinney ◽  
Ellen Sidransky
Keyword(s):  
Cell Types ◽  
Lysosomal Storage Disorders ◽  
Lysosomal Storage ◽  
Lysosomal Disorders ◽  
Lysosomal Dysfunction ◽  
Endosomal Membranes ◽  
A Cell ◽  
The Central Nervous System ◽  
And Function ◽  
Storage Disorders

Exosomes, small membrane-bound organelles formed from endosomal membranes, represent a heterogenous source of biological and pathological biomarkers capturing the metabolic status of a cell. Exosomal cargo, including lipids, proteins, mRNAs, and miRNAs, can either act as inter-cellular messengers or are shuttled for autophagic/lysosomal degradation. Most cell types in the central nervous system (CNS) release exosomes, which serve as long and short distance communicators between neurons, astrocytes, oligodendrocytes, and microglia. Lysosomal storage disorders are diseases characterized by the accumulation of partially or undigested cellular waste. The exosomal content in these diseases is intrinsic to each individual disorder. Emerging research indicates that lysosomal dysfunction enhances exocytosis, and hence, in lysosomal disorders, exosomal secretion may play a role in disease pathogenesis. Furthermore, the unique properties of exosomes and their ability to carry cargo between adjacent cells and organs, and across the blood–brain barrier, make them attractive candidates for use as therapeutic delivery vehicles. Thus, understanding exosomal content and function may have utility in the treatment of specific lysosomal storage disorders. Since lysosomal dysfunction and the deficiency of at least one lysosomal enzyme, glucocerebrosidase, is associated with the development of parkinsonism, the study and use of exosomes may contribute to an improved understanding of Parkinson disease, potentially leading to new therapeutics.

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