Overview of immune abnormalities in lysosomal storage disorders

Rigante, Donato; Cipolla, Clelia; Basile, Umberto; Gulli, Francesca; Savastano, Maria Cristina

doi:10.1016/j.imlet.2017.07.004

Cited by 71 publications

(48 citation statements)

References 64 publications

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“…This negative feedback seems to be an excellent mechanism to control P2X7 receptor activity. Notably, deficiency in acid sphingomyelinase leads to the devastating Niemann-Pick disease that is associated with severe cognitive decline and impaired neuromotor coordination ( Ledesma et al, 2011 ; Rigante et al, 2017 ). Though the exact mechanism remains poorly understood, it is possible that accumulation of SM due to the lack of acid sphingomyelinase activity may hyper-activate P2X7 receptors.…”

Section: Discussionmentioning

confidence: 99%

The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition

Karasawa

Michalski

Mikhelzon

et al. 2017

eLife

122

128

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The P2X7 receptor mediates extracellular ATP signaling implicated in the development of devastating diseases such as chronic pain and cancer. Activation of the P2X7 receptor leads to opening of the characteristic dye-permeable membrane pore for molecules up to ~900 Da. However, it remains controversial what constitutes this peculiar pore and how it opens. Here we show that the panda receptor, when purified and reconstituted into liposomes, forms an intrinsic dye-permeable pore in the absence of other cellular components. Unexpectedly, we found that this pore opens independent of its unique C-terminal domain. We also found that P2X7 channel activity is facilitated by phosphatidylglycerol and sphingomyelin, but dominantly inhibited by cholesterol through direct interactions with the transmembrane domain. In combination with cell-based functional studies, our data suggest that the P2X7 receptor itself constitutes a lipid-composition dependent dye-permeable pore, whose opening is facilitated by palmitoylated cysteines near the pore-lining helix.

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Section: Discussionmentioning

confidence: 99%

The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition

Karasawa

Michalski

Mikhelzon

et al. 2017

eLife

122

128

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“…Many LSDs are associated with immune abnormalities including autoimmune phenomena (reviewed in Rigante et al, 2017;Simonaro, 2016). The autophagy-lysosome system is crucial for infection and immunity, in particular for processing of the major histocompatibility complex class II (MHC-II) and its presentation to CD4 + T cells (Münz, 2012).…”

Section: Immune Responsementioning

confidence: 99%

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

2019

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The pivotal role of lysosomes in cellular processes is increasingly appreciated. An understanding of the balanced interplay between the activity of acidic hydrolases, lysosomal membrane proteins and cytosolic proteins is required. Lysosomal storage diseases (LSDs) are characterized by disturbances in this network and by intralysosomal accumulation of substrates, often only in certain cell types. Even though our knowledge of these diseases has increased and therapies have been established, many aspects of the molecular pathology of LSDs remain obscure. This Review aims to discuss how lysosomal storage affects functions linked to lysosomes, such as membrane repair, autophagy, exocytosis, lipid homeostasis, signalling cascades and cell viability. Therapies must aim to correct lysosomal storage not only morphologically, but reverse its (patho)biochemical consequences. As different LSDs have different molecular causes, this requires custom tailoring of therapies. We will discuss the major advantages and drawbacks of current and possible future therapies for LSDs. Study of the pathological molecular mechanisms underlying these 'experiments of nature' often yields information that is relevant for other conditions found in the general population. Therefore, more common diseases may profit from a correction of impaired lysosomal function.

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“…There are various abnormalities, such as increased production of autoantibodies (Gaucher disease, Fabry disease), increased immune-mediated reactions in MPS, or an inappropriate activation of microglia in neurodegenerative foci of Niemann-Pick disease. 28 The impaired cell metabolism in LSDs leads to disturbances in autophagy, impaired autophagosomelysosome fusion, accumulation of undegraded macromolecules in the cell, dysfunction of other cell organelles such as mitochondria, and manifests with increased expression of chemokines/cytokines, increased signs of inflammation and neovascularization. Especially in Gaucher disease, the consistently increased levels of proinflammatory cytokines and chemokines as well as the chronic stimulation of the immune system may be responsible for the production of monoclonal and polyclonal immunoglobulins, which result in the development of multiple myeloma in these patients.…”

Section: Lysosomal Storage Disorders As Inducers Of Inflammationmentioning

confidence: 99%

“…Especially in Gaucher disease, the consistently increased levels of proinflammatory cytokines and chemokines as well as the chronic stimulation of the immune system may be responsible for the production of monoclonal and polyclonal immunoglobulins, which result in the development of multiple myeloma in these patients. 28 The accumulation of GAGs in MPS starts a cascade of intracellular responses, such as metabolic, inflammatory, and immunological effects in several organs. Especially the immune system and the skeleton share some of the same regulatory molecules, such as classical cytokines, receptor proteins, adaptor proteins, transcription factors, and signal transducers influencing the interplay between bone-forming osteoblasts and bone resorbing osteoclasts, which can be observed in severe changes of bone formation and rheumatoid-like chronic arthritis of many joints with increasing stiffness and contractures.…”

Section: Lysosomal Storage Disorders As Inducers Of Inflammationmentioning

confidence: 99%

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Lysosomes and Their Role in Mucopolysaccharide Disorders: New Insights

Kircher

Taylor

2018

JCS

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Mucopolysaccharidoses (MPS) belong to the group of lysosomal storage diseases and are characterized by the deficiency of lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs). They are caused by inherited enzyme deficiencies that result from mutated genes producing defective enzymes. In MPS, the step-wise degradation process of GAG chains is impaired, and thus pieces of undegraded chains remain in the lysosomes impeding other processes in these cell organelles. Several enzymes—currently 12 are known—are necessary to degrade GAGs to sugars and small chemical substances, such as sulfate- or amino groups, to prepare them for excretion via exocytosis or to reintegrate them into new molecules by recycling. GAGs are major components of the connective tissue but play a role in shaping the vicinity of each cell surface as well; hence, any disturbance in their metabolism causes problems not limited to connective tissue but other tissues and organs. Therefore, MPS are multisystemic diseases involving many organs and restrict a wide range of organ functions. Organomegaly, typical skeletal changes known as “dysostosis multiplex,” excessive storage in the nervous system with neurologic symptoms and impaired cognitive function have been known as the typical symptoms of the first classical MPS types for some time now. Because of new therapies and improved care, the life expectancy of MPS patients has increased significantly. Results of investigations that have only become available recently and new methods allowing for fine-meshed observation have revealed unexpected findings. These outcomes are not limited to excessive storage: patients show unpredictable reactions of the immune system, chronic inflammation, changes in metabolic pathways not directly related to the connective tissue, such as chronic arthritis, osteopenia, Parkinson-like symptoms, signs of dementia, and many more, which suggest that lysosomes have many more roles than just degradation of no longer needed macromolecules.

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Overview of immune abnormalities in lysosomal storage disorders

Cited by 71 publications

References 64 publications

The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition

The P2X7 receptor forms a dye-permeable pore independent of its intracellular domain but dependent on membrane lipid composition

Lysosomal storage disorders – challenges, concepts and avenues for therapy: beyond rare diseases

Lysosomes and Their Role in Mucopolysaccharide Disorders: New Insights

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