-
The EMBO Journal Jul 2023The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players...
The mature mammalian brain connectome emerges during development via the extension and pruning of neuronal connections. Glial cells have been identified as key players in the phagocytic elimination of neuronal synapses and projections. Recently, phosphatidylserine has been identified as neuronal "eat-me" signal that guides elimination of unnecessary input sources, but the associated transduction systems involved in such pruning are yet to be described. Here, we identified Xk-related protein 8 (Xkr8), a phospholipid scramblase, as a key factor for the pruning of axons in the developing mammalian brain. We found that mouse Xkr8 is highly expressed immediately after birth and required for phosphatidylserine exposure in the hippocampus. Mice lacking Xkr8 showed excess excitatory nerve terminals, increased density of cortico-cortical and cortico-spinal projections, aberrant electrophysiological profiles of hippocampal neurons, and global brain hyperconnectivity. These data identify phospholipid scrambling by Xkr8 as a central process in the labeling and discrimination of developing neuronal projections for pruning in the mammalian brain.
Topics: Animals; Mice; Phospholipid Transfer Proteins; Apoptosis Regulatory Proteins; Apoptosis; Phosphatidylserines; Axons; Neuronal Plasticity; Mammals; Membrane Proteins
PubMed: 37211968
DOI: 10.15252/embj.2022111790 -
Cell Communication and Signaling : CCS Feb 2020Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients. To increase the breadth of patients that benefit from... (Review)
Review
Immunotherapy for cancer is making impressive strides at improving survival of a subset of cancer patients. To increase the breadth of patients that benefit from immunotherapy, new strategies that combat the immunosuppressive microenvironment of tumors are needed. Phosphatidylserine (PS) signaling is exploited by tumors to enhance tumor immune evasion and thus strategies to inhibit PS-mediated immune suppression have potential to increase the efficacy of immunotherapy. PS is a membrane lipid that flips to the outer surface of the cell membrane during apoptosis and/or cell stress. Externalized PS can drive efferocytosis or engage PS receptors (PSRs) to promote local immune suppression. In the tumor microenvironment (TME) PS-mediated immune suppression is often termed apoptotic mimicry. Monoclonal antibodies (mAbs) targeting PS or PSRs have been developed and are in preclinical and clinical testing. The TIM (T-cell/transmembrane, immunoglobulin, and mucin) and TAM (Tyro3, AXL, and MerTK) family of receptors are PSRs that have been shown to drive PS-mediated immune suppression in tumors. This review will highlight the development of mAbs targeting PS, TIM-3 and the TAM receptors. Video Abstract.
Topics: Animals; Antineoplastic Agents, Immunological; Humans; Immunotherapy; Neoplasms; Phosphatidylserines; Receptors, Cell Surface; Tumor Microenvironment
PubMed: 32087708
DOI: 10.1186/s12964-020-0521-5 -
Biochimica Et Biophysica Acta Jun 2008In normal healthy cells phosphatidylserine is located in the inner leaflet of the plasma membrane. However, on activated platelets, dying cells and under specific... (Review)
Review
In normal healthy cells phosphatidylserine is located in the inner leaflet of the plasma membrane. However, on activated platelets, dying cells and under specific circumstances also on various types of viable leukocytes phosphatidylserine is actively externalized to the outer leaflet of the plasma membrane. Annexin A5 has the ability to bind in a calcium-dependent manner to phosphatidylserine and to form a membrane-bound two-dimensional crystal lattice. Based on these abilities various functions for extracellular annexin A5 on the phosphatidylserine-expressing plasma membrane have been proposed. In this review we describe possible mechanisms for externalization of annexin A5 and various processes in which extracellular annexin A5 may play a role such as blood coagulation, apoptosis, phagocytosis and formation of plasma membrane-derived microparticles. We further highlight the recent discovery of internalization of extracellular annexin A5 by phosphatidylserine-expressing cells.
Topics: Annexin A5; Apoptosis; Cell Membrane; Crystallization; Humans; Phagocytosis; Phosphatidylserines
PubMed: 18334229
DOI: 10.1016/j.bbamcr.2008.01.030 -
Cell Communication and Signaling : CCS Oct 2019The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other "eat me" signals,... (Review)
Review
The exposure of phosphatidylserine (PS) on the outer plasma membrane has long been considered a unique feature of apoptotic cells. Together with other "eat me" signals, it enables the recognition and phagocytosis of dying cells (efferocytosis), helping to explain the immunologically-silent nature of apoptosis. Recently, however, PS exposure has also been reported in non-apoptotic forms of regulated inflammatory cell death, such as necroptosis, challenging previous dogma. In this review, we outline the evidence for PS exposure in non-apoptotic cells and extracellular vesicles (EVs), and discuss possible mechanisms based on our knowledge of apoptotic-PS exposure. In addition, we examine the outcomes of non-apoptotic PS exposure, including the reversibility of cell death, efferocytosis, and consequent inflammation. By examining PS biology, we challenge the established approach of distinguishing apoptosis from other cell death pathways by AnnexinV staining of PS externalization. Finally, we re-evaluate how PS exposure is thought to define apoptosis as an immunologically silent process distinct from other non-apoptotic and inflammatory cell death pathways. Ultimately, we suggest that a complete understanding of how regulated cell death processes affect the immune system is far from being fully elucidated.
Topics: Animals; Apoptosis; Cell Death; Humans; Inflammation; Phagocytosis; Phosphatidylserines
PubMed: 31665027
DOI: 10.1186/s12964-019-0437-0 -
Cell Communication and Signaling : CCS Jan 2020Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of... (Review)
Review
Phosphatidylserine (PS) is normally located in the inner leaflet of the membrane bilayer of healthy cells, however it is expressed at high levels on the surface of cancer cells. This has allowed for the development of selective therapeutic agents against cancer cells (without affecting healthy cells). SapC-DOPS is a PS-targeting nanovesicle which effectively targets and kills several cancer types including pancreatic, lung, brain, and pediatric tumors. Our studies have demonstrated that SapC-DOPS selectively induces apoptotic cell death in malignant and metastatic cells, whereas untransformed cells remain unaffected due to low surface PS expression. Furthermore, SapC-DOPS can be used in combination with standard therapies such as irradiation and chemotherapeutic drugs to significantly enhance the antitumor efficacy of these treatments. While the PS-targeting nanovesicles are a promising selective therapeutic option for the treatment of cancers, more preclinical studies are needed to fully understand the mechanisms leading to non-apoptotic PS expression on the surface of viable cancer cells and to determine the effectiveness of SapC-DOPS in advanced metastatic disease. In addition, the completion of clinical studies will determine therapeutic effects and drug safety in patients. A phase I clinical trial using SapC-DOPS has been completed on patients with solid tumors and has demonstrated compelling patient outcomes with a strong safety profile. Results from this study are informing future studies with SapC-DOPS. Abstract video.
Topics: Animals; Clinical Trials as Topic; Humans; Nanoparticles; Neoplasms; Phosphatidylserines; Saposins
PubMed: 31918715
DOI: 10.1186/s12964-019-0476-6 -
Journal of Lipid Research Jun 2018This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and...
This article provides a historical account of the discovery, chemistry, and biochemistry of two ubiquitous phosphoglycerolipids, phosphatidylserine (PS) and phosphatidylethanolamine (PE), including the ether lipids. In addition, the article describes the biosynthetic pathways for these phospholipids and how these pathways were elucidated. Several unique functions of PS and PE in mammalian cells in addition to their ability to define physical properties of membranes are discussed. For example, the translocation of PS from the inner to the outer leaflet of the plasma membrane of cells occurs during apoptosis and during some other specific physiological processes, and this translocation is responsible for profound life-or-death events. Moreover, mitochondrial function is severely impaired when the PE content of mitochondria is reduced below a threshold level. The discovery and implications of the existence of membrane contact sites between the endoplasmic reticulum and mitochondria and their relevance for PS and PE metabolism, as well as for mitochondrial function, are also discussed. Many of the recent advances in these fields are due to the use of isotope labeling for tracing biochemical pathways. In addition, techniques for disruption of specific genes in mice are now widely used and have provided major breakthroughs in understanding the roles and metabolism of PS and PE in vivo.
Topics: Animals; History, 19th Century; History, 20th Century; History, 21st Century; Humans; Mitochondria; Phosphatidylethanolamines; Phosphatidylserines
PubMed: 29661786
DOI: 10.1194/jlr.R084004 -
Actas Espanolas de Psiquiatria Sep 2017Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and...
Alzheimer disease and the other neurodegenerative dementias as yet have no curative treatment. For this reason, the prevention of these conditions and non-pharmacological treatments are important fields of research at present. The Mediterranean diet (rich in fruits, vegetables, legumes, and olive oil, with regular fish consumption and low consumption of dairy products and meats) has been shown to reduce the incidence of mild cognitive impairment (MCI) and, probably, the conversion of MCI to dementia. Vitamins, especially vitamin E and the vitamins of the B group, have also been associated with the prevention of cognitive impairment due to their antioxidant effects. Ginkgo biloba is one of the most widely used supplements in the world for cognitive improvement because of its possible effects as a vasodilator and facilitator of cerebral vascularization. Green tea polyphenols have shown beneficial effects in different diseases, including cognitive impairment. Cerebral aging is associated with changes in the lipid composition of neuronal membranes, so it has been suggested that treatment with phospholipids like phosphatidylcholine and phosphatidylserine could favor cognitive improvement. Similarly, polyunsaturated and omega-3 fatty acids, and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplements are associated with a beneficial effect on cognitive function due to the cumulative summation of factors that ultimately favor membrane permeability and neuronal functioning.
Topics: Cognitive Dysfunction; Dietary Supplements; Fatty Acids, Omega-3; Humans; Phosphatidylcholines; Phosphatidylserines; Vitamins
PubMed: 29171642
DOI: No ID Found -
Life Science Alliance Aug 2022The evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the ER and plasma...
The evolutionarily conserved extended synaptotagmin (E-Syt) proteins are calcium-activated lipid transfer proteins that function at contacts between the ER and plasma membrane (ER-PM contacts). However, roles of the E-Syt family members in PM lipid organisation remain incomplete. Among the E-Syt family, the yeast tricalbin (Tcb) proteins are essential for PM integrity upon heat stress, but it is not known how they contribute to PM maintenance. Using quantitative lipidomics and microscopy, we find that the Tcb proteins regulate phosphatidylserine homeostasis at the PM. Moreover, upon heat-induced membrane stress, Tcb3 co-localises with the PM protein Sfk1 that is implicated in PM phospholipid asymmetry and integrity. The Tcb proteins also control the PM targeting of the known phosphatidylserine effector Pkc1 upon heat-induced stress. Phosphatidylserine has evolutionarily conserved roles in PM organisation, integrity, and repair. We propose that phospholipid regulation is an ancient essential function of E-Syt family members required for PM integrity.
Topics: Cell Membrane; Homeostasis; Membrane Proteins; Phosphatidylserines; Phospholipids; Synaptotagmins
PubMed: 35440494
DOI: 10.26508/lsa.202201430 -
Lipids in Health and Disease May 2020Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been...
Recovery of brain DHA-containing phosphatidylserine and ethanolamine plasmalogen after dietary DHA-enriched phosphatidylcholine and phosphatidylserine in SAMP8 mice fed with high-fat diet.
BACKGROUND
Glycerophospholipids were the main components of cerebral cortex lipids, and there was a close association between lipid homeostasis and human health. It has been reported that dietary DHA-enriched phosphatidylcholine (DHA-PC) and phosphatidylserine (DHA-PS) could improve brain function. However, it was unclear that whether supplementation of DHA-PC and DHA-PS could change lipid profiles in the brain of dementia animals.
METHODS
SAMP8 mice was fed with different diet patterns for 2 months, including high-fat diet and low-fat diet. After intervention with DHA-PC and DHA-PS for another 2 months, the lipid profile in cerebral cortex was determined by lipidomics in dementia mice.
RESULTS
High-fat diet could significantly decrease the levels of DHA-containing PS/pPE, DPA-containing PS, and AA-containing PE, which might exhibit the potential of lipid biomarkers for the prevention and diagnosis of AD. Notably, DHA-PC and DHA-PS remarkably recovered the lipid homeostasis in dementia mice. These might provide a potential novel therapy strategy and direction of dietary intervention for patients with cognitive decline.
CONCLUSIONS
DHA-PC and DHA-PS could recover the content of brain DHA-containing PS and pPE in SAMP8 mice fed with high-fat diet.
Topics: Alzheimer Disease; Animals; Cerebral Cortex; Diet, High-Fat; Disease Models, Animal; Docosahexaenoic Acids; Lipidomics; Male; Mice; Phosphatidylcholines; Phosphatidylserines; Plasmalogens
PubMed: 32450867
DOI: 10.1186/s12944-020-01253-3 -
Role of flippases, scramblases and transfer proteins in phosphatidylserine subcellular distribution.Traffic (Copenhagen, Denmark) Jan 2015It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then... (Review)
Review
It is well known that lipids are heterogeneously distributed throughout the cell. Most lipid species are synthesized in the endoplasmic reticulum (ER) and then distributed to different cellular locations in order to create the distinct membrane compositions observed in eukaryotes. However, the mechanisms by which specific lipid species are trafficked to and maintained in specific areas of the cell are poorly understood and constitute an active area of research. Of particular interest is the distribution of phosphatidylserine (PS), an anionic lipid that is enriched in the cytosolic leaflet of the plasma membrane. PS transport occurs by both vesicular and non-vesicular routes, with members of the oxysterol-binding protein family (Osh6 and Osh7) recently implicated in the latter route. In addition, the flippase activity of P4-ATPases helps build PS membrane asymmetry by preferentially translocating PS to the cytosolic leaflet. This asymmetric PS distribution can be used as a signaling device by the regulated activation of scramblases, which rapidly expose PS on the extracellular leaflet and play important roles in blood clotting and apoptosis. This review will discuss recent advances made in the study of phospholipid flippases, scramblases and PS-specific lipid transfer proteins, as well as how these proteins contribute to subcellular PS distribution.
Topics: Adenosine Triphosphatases; Animals; Biological Transport; Cell Membrane; Endoplasmic Reticulum; Humans; Phosphatidylserines; Phospholipids
PubMed: 25284293
DOI: 10.1111/tra.12233