Lysosome-targeted lipid probes reveal sterol transporters NPC1 and LIMP2 as sphingosine transporters

Lysosomes are central catabolic organelles involved in lipid homeostasis and their dysfunction is associated with pathologies ranging from lysosomal storage disorders to common neurodegenerative diseases. The mechanism of lipid efflux from lysosomes is well understood for cholesterol, while the export of other lipids, particularly sphingosine, is less well studied. To overcome this knowledge gap, we have developed functionalized sphingosine and cholesterol probes that allow us to follow their metabolism, protein interactions as well as their subcellular localization. These probes feature a modified cage group for lysosomal targeting and controlled release of the active lipids with high temporal precision. An additional photo-crosslinkable group allowed for the discovery of lysosomal interactors for both sphingosine and cholesterol. In this way, we found that two lysosomal cholesterol transporters, NPC1 and LIMP-2/SCARB2, also directly bind to sphingosine. In addition, we showed that absence of either protein leads to lysosomal sphingosine accumulation which suggests a sphingosine transport role of both proteins. Furthermore, artificial elevation of lysosomal sphingosine levels impaired cholesterol efflux, consistent with sphingosine and cholesterol sharing a common export mechanism.

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Lipids, lysosomes and mitochondria: insights into Lewy body formation from rare monogenic disorders

Acta Neuropathologica ◽

10.1007/s00401-021-02266-7 ◽

2021 ◽

Cited By ~ 1

Author(s):

Daniel Erskine ◽

David Koss ◽

Viktor I. Korolchuk ◽

Tiago F. Outeiro ◽

Johannes Attems ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Bodies ◽

Mitochondrial Diseases ◽

Model Systems ◽

Lipid Homeostasis ◽

Lysosomal Storage ◽

Iron Storage ◽

Monogenic Disorders ◽

Storage Disorders

AbstractAccumulation of the protein α-synuclein into insoluble intracellular deposits termed Lewy bodies (LBs) is the characteristic neuropathological feature of LB diseases, such as Parkinson’s disease (PD), Parkinson’s disease dementia (PDD) and dementia with LB (DLB). α-Synuclein aggregation is thought to be a critical pathogenic event in the aetiology of LB disease, based on genetic analyses, fundamental studies using model systems, and the observation of LB pathology in post-mortem tissue. However, some monogenic disorders not traditionally characterised as synucleinopathies, such as lysosomal storage disorders, iron storage disorders and mitochondrial diseases, appear disproportionately vulnerable to the deposition of LBs, perhaps suggesting the process of LB formation may be a result of processes perturbed as a result of these conditions. The present review discusses biological pathways common to monogenic disorders associated with LB formation, identifying catabolic processes, particularly related to lipid homeostasis, autophagy and mitochondrial function, as processes that could contribute to LB formation. These findings are discussed in the context of known mediators of α-synuclein aggregation, highlighting the potential influence of impairments to these processes in the aetiology of LB formation.

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Cathepsins in the Pathophysiology of Mucopolysaccharidoses: New Perspectives for Therapy

Cells ◽

10.3390/cells9040979 ◽

2020 ◽

Vol 9 (4) ◽

pp. 979 ◽

Cited By ~ 5

Author(s):

Valeria De Pasquale ◽

Anna Moles ◽

Luigi Michele Pavone

Keyword(s):

Molecular Mechanisms ◽

Protein Processing ◽

Lysosomal Storage ◽

Therapeutic Approaches ◽

Kidney Dysfunction ◽

Nuclear Membranes ◽

Intracellular Organelles ◽

Primary Focus ◽

Storage Disorders

Cathepsins (CTSs) are ubiquitously expressed proteases normally found in the endolysosomal compartment where they mediate protein degradation and turnover. However, CTSs are also found in the cytoplasm, nucleus, and extracellular matrix where they actively participate in cell signaling, protein processing, and trafficking through the plasma and nuclear membranes and between intracellular organelles. Dysregulation in CTS expression and/or activity disrupts cellular homeostasis, thus contributing to many human diseases, including inflammatory and cardiovascular diseases, neurodegenerative disorders, diabetes, obesity, cancer, kidney dysfunction, and others. This review aimed to highlight the involvement of CTSs in inherited lysosomal storage disorders, with a primary focus to the emerging evidence on the role of CTSs in the pathophysiology of Mucopolysaccharidoses (MPSs). These latter diseases are characterized by severe neurological, skeletal and cardiovascular phenotypes, and no effective cure exists to date. The advance in the knowledge of the molecular mechanisms underlying the activity of CTSs in MPSs may open a new challenge for the development of novel therapeutic approaches for the cure of such intractable diseases.

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The role of current biomarkers in the management of lysosomal storage disorders

Clinical Therapeutics ◽

10.1016/s0149-2918(08)00366-4 ◽

2008 ◽

Vol 30 ◽

pp. S90-S91 ◽

Cited By ~ 1

Author(s):

I MAIRE ◽

N GUFFON ◽

M PIRAUD ◽

R FROISSART

Keyword(s):

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Storage Disorders

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Insight into the Role of Extracellular Vesicles in Lysosomal Storage Disorders

Genes ◽

10.3390/genes10070510 ◽

2019 ◽

Vol 10 (7) ◽

pp. 510 ◽

Cited By ~ 17

Author(s):

Brunella Tancini ◽

Sandra Buratta ◽

Krizia Sagini ◽

Eva Costanzi ◽

Federica Delo ◽

...

Keyword(s):

Extracellular Vesicles ◽

Lysosomal Storage Disorders ◽

Stress Conditions ◽

Lysosomal Storage ◽

Pharmacological Agents ◽

Lysosomal System ◽

Protein Nucleic Acid ◽

Intracellular Storage ◽

Storage Disorders

Extracellular vesicles (EVs) have received increasing attention over the last two decades. Initially, they were considered as just a garbage disposal tool; however, it has progressively become clear that their protein, nucleic acid (namely miRNA and mRNA), and lipid contents have signaling functions. Besides, it has been established that cells release different types of vesicular structures for which characterization is still in its infancy. Many stress conditions, such as hypoxia, senescence, and oncogene activation have been associated with the release of higher levels of EVs. Further, evidence has shown that autophagic–lysosomal pathway abnormalities also affect EV release. In fact, in neurodegenerative diseases characterized by the accumulation of toxic proteins, although it has not become clear to what extent the intracellular storage of undigested materials itself has beneficial/adverse effects, these proteins have also been shown to be released extracellularly via EVs. Lysosomal storage disorders (LSDs) are characterized by accumulation of undigested substrates within the endosomal–lysosomal system, due either to genetic mutations in lysosomal proteins or to treatment with pharmacological agents. Here, we review studies investigating the role of lysosomal and autophagic dysfunction on the release of EVs, with a focus on studies exploring the release of EVs in LSD models of both genetic and pharmacological origin. A better knowledge of EV-releasing pathways activated in lysosomal stress conditions will provide information on the role of EVs in both alleviating intracellular storage of undigested materials and spreading the pathology to the neighboring tissue.

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

Brain Communications ◽

10.1093/braincomms/fcaa200 ◽

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.

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Autologous transplantation of human genome-edited hematopoietic stem cells for lysosomal storage disorders: the role of pre-transplant conditioning

Molecular Genetics and Metabolism ◽

10.1016/s1096-7192(21)00174-8 ◽

2021 ◽

Vol 132 ◽

pp. S62

Author(s):

Natalia Gomez-Ospina ◽

Pasqualina Colella ◽

Shaukat Khan ◽

Shunji Tomatsu ◽

Edina Poletto

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Human Genome ◽

Autologous Transplantation ◽

Lysosomal Storage Disorders ◽

Lysosomal Storage ◽

Hematopoietic Stem ◽

Storage Disorders

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Role of lysosomes in physiological activities, diseases, and therapy

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01087-1 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Ziqi Zhang ◽

Pengfei Yue ◽

Tianqi Lu ◽

Yang Wang ◽

Yuquan Wei ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Growth Regulation ◽

Malignant Tumors ◽

Autoimmune Disorders ◽

Lysosomal Storage Disorders ◽

Nutrient Sensing ◽

Inflammasome Activation ◽

Lysosomal Storage ◽

Storage Disorders

AbstractLong known as digestive organelles, lysosomes have now emerged as multifaceted centers responsible for degradation, nutrient sensing, and immunity. Growing evidence also implicates role of lysosome-related mechanisms in pathologic process. In this review, we discuss physiological function of lysosomes and, more importantly, how the homeostasis of lysosomes is disrupted in several diseases, including atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, lysosomal storage disorders, and malignant tumors. In atherosclerosis and Gaucher disease, dysfunction of lysosomes changes cytokine secretion from macrophages, partially through inflammasome activation. In neurodegenerative diseases, defect autophagy facilitates accumulation of toxic protein and dysfunctional organelles leading to neuron death. Lysosomal dysfunction has been demonstrated in pathology of pancreatitis. Abnormal autophagy activation or inhibition has been revealed in autoimmune disorders. In tumor microenvironment, malignant phenotypes, including tumorigenesis, growth regulation, invasion, drug resistance, and radiotherapy resistance, of tumor cells and behaviors of tumor-associated macrophages, fibroblasts, dendritic cells, and T cells are also mediated by lysosomes. Based on these findings, a series of therapeutic methods targeting lysosomal proteins and processes have been developed from bench to bedside. In a word, present researches corroborate lysosomes to be pivotal organelles for understanding pathology of atherosclerosis, neurodegenerative diseases, autoimmune disorders, pancreatitis, and lysosomal storage disorders, and malignant tumors and developing novel therapeutic strategies.

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