Biology subjects

Yue, Z.

Publications and source records attributed to Yue, Z..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration

Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.

cell biology↗

bioRxiv2023

Sleepiness, not total sleep amount, increases seizure risk

Sleep loss has been associated with increased seizure risk since antiquity. Despite this observation standing the test of time, how poor sleep drives susceptibility to seizures remains unclear. To identify underlying mechanisms, we restricted sleep in Drosophila epilepsy models and developed a method to identify spontaneous seizures using quantitative video tracking. Here we find that sleep loss exacerbates seizures but only when flies experience increased sleep need, or sleepiness, and not necessarily with reduced sleep quantity. This is supported by the paradoxical finding that acute activation of sleep-promoting circuits worsens seizures, because it increases sleep need without changing sleep amount. Sleep-promoting circuits become hyperactive after sleep loss and are associated with increased whole-brain activity. During sleep restriction, optogenetic inhibition of sleep-promoting circuits to reduce sleepiness protects against seizures. Downregulation of the 5HT1A serotonin receptor in sleep-promoting cells mediates the effect of sleep need on seizures, and we identify an FDA-approved 5HT1A agonist to mitigate seizures. Our findings demonstrate that while homeostatic sleep is needed to recoup lost sleep, it comes at the cost of increasing seizure susceptibility. We provide an unexpected perspective on interactions between sleep and seizures, and surprisingly implicate sleep- promoting circuits as a therapeutic target for seizure control.

neuroscience↗

bioRxiv2023

Whole genome sequencing reveals autooctoploidy in the Chinese sturgeon and its evolutionary trajectories

The Order Acipenseriformes, which include sturgeons and paddlefishes, represent "living fossils" with complex genomes that are good models for understanding whole genome duplication (WGD) and ploidy evolution in fishes. Here we sequenced and assembled the first high-quality chromosome-level genome for the complex octoploid Acipenser sinensis (Chinese sturgeon), a critically endangered species that also represents a poorly understood ploidy group in Acipenseriformes. Our results show that A. sinensis is a complex autooctoploid species containing four kinds of octovalents (8 n), a hexavalent (6 n), two tetravalents (4 n), and a divalent (2 n). We propose based on an analysis taking into account delayed rediploidization that its octoploid genome composition results from two rounds of homologous whole genome duplications (WGDs), and further provide insight into the timing of its ploidy evolution. This study provides the first octoploid genome resource of Acipenseriformes for understanding ploidy composition and evolutionary trajectories of polyploidy fishes.

genomics↗

bioRxiv2023

Sleep and memory consolidation are linked by RNA processing genes in the Drosophila mushroom body

Memory consolidation in Drosophila can be sleep-dependent or sleep-independent, depending on the availability of food. The anterior posterior (ap) alpha'/beta' ('/{beta}') neurons of the mushroom body (MB) are required for sleep-dependent memory consolidation in flies fed after training. These neurons are also involved in the increase of sleep after training, suggesting a coupling of sleep and memory. To better understand the mechanisms underlying sleep and memory consolidation initiation, we analyzed the transcriptome of ap '/{beta}' neurons one hour after appetitive memory conditioning. A small number of genes, enriched in RNA processing functions, were differentially expressed in flies fed after training relative to trained and starved flies or untrained flies. Knockdown of each of these differentially expressed genes in the ap '/{beta}' neurons revealed notable sleep phenotypes for Polr1F and Regnase-1, both of which decrease in expression after conditioning. Knockdown of Polr1F, a regulator of ribosome RNA transcription, in adult flies promotes sleep and increases pre-ribosome RNA expression as well as overall translation, supporting a function for Polr1F downregulation in sleep-dependent memory. Conversely, while constitutive knockdown of Regnase-1, an mRNA decay protein localized to the ribosome, reduces sleep, adult specific knockdown suggests that effects of Regnase-1 on sleep are developmental in nature. We further tested the role of each gene in memory consolidation. Knockdown of Polr1F does not affect memory, which may be expected from its downregulation during memory consolidation. Regnase-1 knockdown in ap '/{beta}' neurons impairs all memory, including short-term, implicating Regnase-1 in memory, but leaving open the question of why it is downregulated during sleep-dependent memory. Overall, our findings demonstrate that the expression of RNA processing genes is modulated during sleep-dependent memory and, in the case of Polr1F, this modulation likely contributes to increased sleep.

neuroscience↗

bioRxiv2023

Rit2 loss in dopaminergic neurons drives a progressive Parkinsonian phenotype

Parkinsons disease (PD) is the second most prevalent neurodegenerative disease and arises from dopamine (DA) neuron death selectively in the substantia nigra pars compacta (SNc). Rit2 is a reported PD risk allele, and recent single cell transcriptomic studies identified a major RIT2 cluster in PD DA neurons, potentially linking Rit2 expression loss to a PD patient cohort. However, it is still unknown whether Rit2 loss itself is causative for PD or PD-like symptoms. Here we report that conditional Rit2 silencing in mouse DA neurons drove motor dysfunction that occurred earlier in males than females and was rescued at early stages by either inhibiting the DA transporter (DAT) or with L-DOPA treatment. Motor dysfunction was accompanied by decreased DA release, striatal DA content, phenotypic DAergic markers, DA neurons, and DAergic terminals, with increased pSer129-alpha synuclein and pSer935-LRRK2 expression. These results provide the first evidence that Rit2 loss is causal for SNc cell death and a PD-like phenotype, and reveal key sex-specific differences in the response to Rit2 loss.

neuroscience↗

bioRxiv2022

Integrated proteomics reveals the landscape of autophagy degradation in human neurons and autophagy receptors regulating neuronal activity

Autophagy is a catabolic and self-degradative process crucial for maintaining cellular homeostasis. Malfunctional autophagy is implicated in neurodevelopmental and neurodegenerative diseases. However, the exact role and targets of autophagy in human neurons remain elusive. Here we reported a systematic investigation of neuronal autophagy targets through integrated proteomics. Deep proteomic profiling of multiple autophagy-deficient lines of human induced neurons, mouse brains, and LC3-interactome uncovers a role of neuronal autophagy in targeting primarily endoplasmic reticulum (ER), mitochondria, endosome, Golgi apparatus, synaptic vesicle (SV) proteins, and cAMP-PKA pathway, for degradation. Tubular ER and specific SV proteins are significant autophagy cargos in the axons. Functional validation identified calumenin as an ER resident autophagy receptor and illuminated a role of autophagy in regulating PKA and neuronal activity through AKAP11-mediated degradation. Our study thus reveals the landscape of autophagy degradation in human neurons and offers molecular insight into mechanisms of neurological disorders linked to autophagy deficiency. HighlightO_LIIntegrated proteomics reveals the landscape of autophagy degradation in human neurons C_LIO_LIAutophagy clears tubular ER and selective ER and synaptic vesicle proteins in neurons C_LIO_LICalumenin is an ER resident autophagy receptor C_LIO_LIAutophagy controls PKA pathway and neuronal activity through autophagy receptor AKAP11 C_LI

neuroscience↗

bioRxiv2022

Nuclear autophagy interactome unveils WSTF as a constitutive nuclear inhibitor of inflammation

Macroautophagy (hereafter referred to as autophagy) degrades a variety of cellular components. A poorly understood area is autophagic degradation of nuclear substrates, or "nuclear autophagy". It remains unclear what can be degraded by autophagy from the mammalian nuclei. We began our study by investigating the nuclear binding partners of ATG8 family proteins that play important roles in recognizing autophagy substrates. We systematically evaluated the ATG8 nuclear interactome in primary human cells and in mouse brain, identifying hundreds of novel interactions. We continued our study by evaluating the nuclear proteomes of cellular senescence, a stable form of cell cycle arrest program associated with inflammation, in which nuclear autophagy is involved. Combined with the ATG8 nuclear interactome data, we identified WSTF, a component of the ISWI chromatin remodeling complex, as a novel substrate of nuclear autophagy. The degradation of WSTF, mediated by a direct interaction with the GABARAP isoform of ATG8, promotes chromatin accessibility of inflammatory genes and induces senescence-associated inflammation. Furthermore, WSTF directly binds the p65 subunit of NF-{kappa}B and inhibits its acetylation, thus blocking inflammatory gene expression in the setting of senescence, cancer, and pathogen infection. In addition, we show that loss of WSTF is required for the immuno-surveillance of oncogenic Ras in mouse liver; forced expression of WSTF inhibited tumor-suppressive inflammation and led to the development of liver tumors. Taken together, our study provides a global view of mammalian nuclear autophagy and reveals a novel nuclear inhibitor of inflammation implicated in diverse pathological contexts. Targeting WSTF may be broadly valuable as therapeutic intervention of inflammatory diseases.

cell biology↗

bioRxiv2022

Exploring high-quality microbial genomes by assembly of linked-reads with high barcode specificity using deep learning

Despite long-read sequencing enables to generate complete genomes of unculturable microbes, its high cost hinders its widespread application in large cohorts. An alternative method is to assemble short-reads with long-range connectivity, which can be a cost-effective way to generate high-quality microbial genomes. We developed Pangaea to improve metagenome assembly using short-reads with physical or virtual barcodes. It adopts a deep-learning-based binning algorithm to assemble the co-barcoded reads with similar sequence contexts and abundances to improve assemblies of high- and medium-abundance microbes. Pangaea also leverages a multi-thresholding reassembly strategy to refine assembly for low-abundance microbes. We benchmarked Pangaea with linked-reads and a combination of short- and long-reads from mock communities and human gut metagenomes. Pangaea achieved significantly higher contig continuity as well as more near-complete metagenome-assembled genomes (NCMAGs) than the existing assemblers. Pangaea was also observed to generate three complete and circular NCMAGs on the human gut microbiomes.

genomics↗

bioRxiv2022

Ecdysone acts through cortex glia to regulate sleep in Drosophila

Steroid hormones are attractive candidates for transmitting long-range signals to affect behavior. These lipid-soluble molecules derived from dietary cholesterol easily penetrate the brain and act through nuclear hormone receptors (NHRs) that function as transcription factors. To determine the extent to which NHRs affect sleep: wake cycles, we knocked down each of the 18 highly conserved NHRs found in Drosophila adults and report that the ecdysone receptor (EcR) and its direct downstream NHR Eip75B (E75) act in glia to regulate the rhythm and amount of sleep. Halloween genes, a set of ecdysone synthesis genes, have little to no expression in the fly brain, while mRNA levels of the ecdysone target E75 cycle in the fly head, suggesting that glial ecdysone comes from the periphery and may enter the brain more at night. Anti-EcR staining localizes to the cortex glia in the brain and functional screening of glial subtypes revealed that EcR functions in adult cortex glia to affect sleep. Cortex glia are implicated in lipid metabolism, which appears to be relevant for actions of ecdysone as ecdysone treatment reduces lipid droplet size in these cells. In addition, sleep-promoting effects of exogenous ecdysone are diminished in Lsd-2 mutant flies, which are lean and deficient in lipid accumulation. We propose that ecdysone is a systemic secreted factor that modulates sleep by stimulating lipid metabolism in cortex glia. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/505204v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@5ab387org.highwire.dtl.DTLVardef@c08619org.highwire.dtl.DTLVardef@1a3fcbaorg.highwire.dtl.DTLVardef@1251f5b_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIGlial knockdown of ecdysone inducible NHRs reduces sleep. C_LIO_LIThe ecdysone receptor (EcR) and its downstream target E75 function in cortex glia to modulate sleep. C_LIO_LIEcdysone synthesis genes are not expressed in the fly brain, suggesting that glial ecdysone comes from the periphery. C_LIO_LIEcdysone promotes sleep by mobilizing lipid droplets stored mainly in glia. C_LI

genetics↗

bioRxiv2022

K2P channel TWK-40 Regulates a Rhythmic Behavior in C. elegans

Leak potassium (K+) currents, conducted by two-pore domain K+ (K2P) channels, are critical for the stabilization of the membrane potential. The effect of K2P channels on motor rhythm remains enigmatic. We show here that the K2P TWK-40 regulates the rhythmic defecation motor program (DMP) in Caenorhabditis elegans. Disrupting TWK-40 suppresses the expulsion defects of nlp-40 and aex-2 mutants. By contrast, a gain-of-function (gf) mutant of twk-40 significantly reduces the expulsion frequency per DMP cycle. In situ whole-cell patch clamping demonstrates that TWK-40 forms an outward current that hyperpolarize the resting membrane potential of DVB neuron. In addition, TWK-40 substantially contributes to the rhythmic activity of DVB. Specifically, DVB Ca2+ oscillations exhibit obvious defects in twk-40 mutants. Expression of TWK-40(gf) in DVB recapitulates the expulsion deficiency of the twk-40(gf) mutant, and inhibits DVB Ca2+ oscillations in both wild-type and twk-40(lf) animals. Moreover, DVB innervated enteric muscles also exhibit rhythmic Ca2+ defects. Taken together, these results demonstrate that TWK-40 is an essential neuronal inhibitor of DMP, thus revealing a cellular mechanism linking leak K2P channels with rhythmic motor activity.

neuroscience↗

bioRxiv2022

Single-cell Transcriptomic Atlas of the Human Substantia Nigra in Parkinson's Disease

Parkinsons disease (PD) is a common and complex neurodegenerative disorder. Loss of neuromelanin-containing dopaminergic (DA) neurons in the substantia nigra (SN) is a hallmark of PD neuropathology; the etiology of PD remains unclear. Single-cell (-nucleus) RNA sequencing (sc or snRNAseq) has significantly advanced our understanding of neurodegenerative diseases including Alzheimers, but limited progress has been made in PD. Here we generated by far the largest snRNAseq data of high-quality 315,867 nuclei from the human SN including 9 healthy controls and 23 idiopathic PD cases across different Braak stages. Clustering analysis identified major brain cell types including DA neurons, excitatory neurons, inhibitory neurons, glial cells, endothelial, pericytes, fibroblast and T-cells in the human SN. By combining immunostaining and validating against the datasets from independent cohorts, we identified three molecularly distinct subtypes of DA-related neurons, including a RIT2-enriched population, in human aged SN. All DA neuron subtypes degenerated in PD, whereas the composition of non-neuronal cell clusters including major glial types showed little change. Our study delineated cell-type-specific PD-linked gene expression in the SN and their alterations in PD. Examination of cell-type-based transcriptomic changes suggests the complexity and diversity of molecular mechanisms of PD. Analysis of the remaining DA neurons of the three subtypes from PD demonstrated alterations of common gene sets associated with neuroprotection. Our findings highlight the heterogeneity of DA neurons in the human SN and suggest molecular basis for vulnerability and resilience of human DA neurons in PD. Our cohort thus provides a valuable resource for dissecting detailed mechanisms of DA neuron degeneration and identifying new neuroprotective strategies for PD.

neuroscience↗

bioRxiv2022

Phospholipase Cβ2 Promotes Vascular Endothelial Growth Factor Induced Vascular Permeability

BackgroundRegulation of vascular permeability (VP) is critical to maintaining tissue metabolic homeostasis. Vascular endothelial growth factor (VEGF) is a key stimulus of VP in acute and chronic diseases including ischemia reperfusion injury, sepsis and cancer. Identification of novel regulators of VP would allow for the development of effective targeted therapeutics for patients with unmet medical need. MethodsIn vitro and in vivo models of VEGFA-induced vascular permeability, pathological permeability, quantitation of intracellular calcium release and cell entry, and PIP2 levels were evaluated with and without modulation of PLC{beta}2. ResultsGlobal knock-out of PLC{beta}2 in mice resulted in blockade of VEGFA-induced vascular permeability in vivo and trans-endothelial permeability in primary lung endothelial cells. Further work in an immortalized human microvascular cell line modulated with stable knock-down of PLC{beta}2 recapitulated the observations in the mouse model and primary cell assays. Additionally, loss of PLC{beta}2 limited both intracellular release and extracellular entry of calcium following VEGF stimulation as well as reduced basal and VEGFA-stimulated levels of PIP2 compared to control cells. Finally, loss of PLC{beta}2 in both a hyperoxia induced lung permeability model and a cardiac ischemia:reperfusion model resulted in improved animal outcomes when compared to WT controls. ConclusionsThe results implicate PLC{beta}2 as a key positive regulator of VEGF-induced VP through regulation of both calcium flux and PIP2 levels at the cellular level. Targeting of PLC{beta}2 in a therapeutic setting may provide a novel approach to regulating vascular permeability in patients. Graphic Abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY HighlightsO_LIPLC{beta}2 promotes VEGFA induced vascular permeability. C_LIO_LILoss of PLC{beta}2 prevents VEGFA vascular permeability via repression of cellular calcium flux and membrane PIP2 levels. C_LIO_LILoss of PLC{beta}2 reduces vascular permeability and improves outcomes in a hyperoxic lung damage model and a cardiac ischemia:reperfusion model in vivo. C_LIO_LITargeting PLC{beta}2 inhibition may lead to a novel therapeutic for diseases such as stroke and myocardial infarction. C_LI

cell biology↗

bioRxiv2022

Three amphioxus reference genomes reveal gene and chromosome evolution of chordates

The slow-evolving invertebrate amphioxus has an irreplaceable role in advancing our understanding into the vertebrate origin and innovations. Here we resolve the nearly complete chromosomal genomes of three amphioxus species, one of which best recapitulates the 17 chordate ancestor linkage groups. We reconstruct the fusions, retention or rearrangements between descendants of whole genome duplications (WGDs), which gave rise to the extant microchromosomes likely existed in the vertebrate ancestor. Similar to vertebrates, the amphioxus genome gradually establishes its 3D chromatin architecture at the onset of zygotic activation, and forms two topologically associated domains at the Hox gene cluster. We find that all three amphioxus species have ZW sex chromosomes with little sequence differentiation, and their putative sex-determining regions are nonhomologous to each other. Our results illuminate the unappreciated interspecific diversity and developmental dynamics of amphioxus genomes, and provide high-quality references for understanding the mechanisms of chordate functional genome evolution.

evolutionary biology↗

bioRxiv2021

Ion Transport, Selectivity, and Electronic Polarization in Fluoride Channels

Fluoride channels (Fluc) export toxic F- from the cytoplasm. Crystallography and mutagenesis have identified several conserved residues crucial for fluoride transport, but the permeation mechanism at the molecular level has remained elusive. Herein we have applied constant-pH molecular dynamics and free energy sampling methods to investigate fluoride permeation through a Fluc protein from Escherichia coli. We find that fluoride is facile to permeate in its charged form, i.e., F-, by traversing through a non-bonded network. The extraordinary F- selectivity is gained by the hydrogen-bonding capability of the central binding site and the Coulombic filter at the channel entrance. The F- permeation rate calculated using an electronically polarizable force field is significantly more accurate compared to the experimental value than that calculated using a more standard additive force field, suggesting an essential role for electronic polarization in the F- - Fluc interactions. O_TEXTBOXSIGNIFICANCE A comprehensive atomistic-level computational study is presented of the mechanism of fluoride permeation through fluoride channels. The mechanism of fluoride permeation of the F- anion is established and the microscopic determinants of F- selectivity revealed. The essential nature of electronic polarization during F- permeation is also demonstrated through the computational modeling. C_TEXTBOX

biophysics↗

bioRxiv2021

Escape Steering by Cholecystokinin Peptidergic Signaling

Escape is an evolutionarily conserved and essential avoidance response. Considered to be innate, most studies on escape responses focused on hard-wired circuits. We report here that peptidergic signaling is an integral and necessary component of the Caenorhabditis elegans escape circuit. Combining genetic screening, electrophysiology and calcium imaging, we reveal that a neuropeptide NLP-18 and its cholecystokinin receptor CKR-1 enable the escape circuit to execute a full omega ({Omega}) turn, the last motor step where the animal robustly steers away from its original trajectory. We demonstrate in vivo and in vitro that CKR-1 is a Gq protein coupled receptor for NLP-18. in vivo, NLP-18 is mainly secreted by the gustatory sensory neuron (ASI) to activate CKR-1 in the head motor neuron (SMD) and the turn-initiating interneuron (AIB). Removal of NLP-18, removal of CKR-1, or specific knockdown of CKR-1 in SMD or AIB neurons lead to shallower turns hence less robust escape steering. Consistently, elevation of head motor neuron (SMD)s Ca2+ transients during escape steering is attenuated upon the removal of NLP-18 or CKR-1. in vitro, synthetic NLP-18 directly evokes CKR-1-dependent currents in oocytes and CKR-1-dependent Ca2+ transients in SMD. Thus, cholecystokinin signaling modulates an escape circuit to generate robust escape steering.

neuroscience↗

bioRxiv2021

Proton Coupling and the Multiscale Kinetic Mechanism of a Peptide Transporter

Proton coupled peptide transporters (POTs) are crucial for the uptake of di- and tri-peptides as well as drug and pro-drug molecules in prokaryotes and eukaryotic cells. We illustrate from multiscale modeling how transmembrane proton flux couples within a POT protein to drive essential steps of the full functional cycle: 1) protonation of a glutamate on transmembrane helix (TM) 7 opens the extracellular gate, allowing ligand entry; 2) inward proton flow induces the cytosolic release of ligand by varying the protonation state of a second conserved glutamate on TM10; 3) proton movement between TM7 and TM10 is thermodynamically driven and kinetically permissible via water proton shuttling without the participation of ligand. Our results, for the first time, give direct computational confirmation for the alternating access model of POTs, and point to a quantitative multiscale kinetic picture of the functioning protein mechanism. SIGNIFICANCEProton-coupled peptide transporters (POTs) utilize transmembrane proton gradient to deliver small peptides and peptide-like drug molecules into cells. Despite extensive biochemical and structural studies, major question regarding protonation-induced shift from inward-facing state to outward-facing state remains obscure. Here, we report direct evidence through multiscale simulations that the extracellular salt bridge controls the outward-open conformational transition of POTs, and how proton influx through POTs couples ligand transport. The computational modeling also suggests a multiscale kinetic mechanism of POTs.

biophysics↗

bioRxiv2021

TRPM2 deficiency protects against atherosclerosis by inhibiting TRPM2-CD36 inflammatory axis in macrophages

Atherosclerosis is the major cause of ischemic heart diseases and ischemic brain stroke, which are the leading causes of mortality worldwide. The central pathological features of atherosclerosis include macrophage infiltration and foam cell formation. However, the detailed mechanisms regulating these two processes remain unclear. Here we show that oxidative stress-activated Ca2+-permeable TRPM2 plays a key role in the pathogenesis of atherosclerosis. Trpm2 deletion produces a potent protective effect against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD), as evidenced by reduced atherosclerotic plaque burden, decreased macrophage load and suppressed inflammasome activation in the vessel wall. Moreover, we show that Trpm2 deletion or inhibition reduces oxidized low-density lipoprotein (oxLDL) uptake by macrophages, suppresses macrophage infiltration induced by monocyte chemoattractant protein-1 (MCP1), and prevents the impairment of macrophage emigration caused by oxLDL. Intriguingly, we uncover that activation of CD36, an oxLDL receptor, can promote the activation of TRPM2, and vice versa, the CD36-mediated inflammatory cascade in atherosclerosis is dependent on TRPM2. In transfected HEK293T cells, CD36 ligands oxLDL and TSP1 induce TRPM2 activation in a CD36-dependent manner. Deleting Trpm2 or inhibiting TRPM2 activity in cultured macrophages suppresses the CD36 signaling cascade induced by oxLDL and TSP1. Our studies establish TRPM2-CD36 axis as a new mechanism underlying atherogenesis, and suggest TRPM2 as an effective therapeutic target for atherosclerosis. HIGHLIGHTSO_LITrpm2 deletion protects against atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD) C_LIO_LITrpm2 deficiency reduces atherosclerotic lesions by minimizing foam cell formation, inhibiting macrophage infiltration and preserving macrophage emigration C_LIO_LITRPM2 activation is required for CD36-induced oxLDL uptake and subsequent inflammatory responses C_LIO_LIThe ligands of CD36, oxLDL and TSP1, activate TRPM2, thereby perpetuating TRPM2-CD36 inflammatory cycle in atherogenesis cascade C_LIO_LIOur data establish TRPM2-CD36 axis as a new atherogenesis mechanism and TRPM2 as a novel therapeutic target for atherosclerosis C_LI O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY TRPM2-mediated Ca2+ signal is essential for CD36 induced oxLDL uptake and atherosclerosis in ApoE-/- mice fed with a high-fat diet (HFD). The activation of CD36 and TRPM2 form a positive feedback loop in atherogenesis. C_FIG_DISPLAY

physiology↗

bioRxiv2021

Functional coupling of TRPM2 and NMDARs exacerbates excitotoxicity in ischemic brain injury

Excitotoxicity caused by NMDA receptors (NMDARs) is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical ischemic stroke trials. Here we reveal an unexpected mechanism underlying NMDARs-mediated neurotoxicity, which leads to identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDARs excitotoxicity upon ischemic insults is mediated by physical and functional coupling to TRPM2. The physical interaction of TRPM2 with NMDARs results in markedly increase in the surface expression of NMDARs, leading to enhanced NMDAR function and increased neuronal death. We identified a specific NMDAR-interacting domain on TRPM2, and developed a cell-permeable peptide to uncouple TRPM2-NMDARs. The disrupting-peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to eliminate excitotoxic neuronal death without directly targeting NMDARs. HIGHLIGHTSO_LITRPM2 physically and functionally interacts with NMDARs C_LIO_LIInteraction of TRPM2 with NMDARs exacerbates NMDARs extrasynaptic excitotoxicity by increasing NMDARs surface expression during ischemic injury C_LIO_LITRPM2 recruits PKC{gamma} to the interacting complexes to increase NMDARs surface expression C_LIO_LIUncoupling the interaction between TRPM2 and NMDARs with a disrupting peptide (TAT-EE3) protects neurons against ischemic stroke in vitro and in vivo C_LI GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/454247v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@e618c5org.highwire.dtl.DTLVardef@646350org.highwire.dtl.DTLVardef@b4478corg.highwire.dtl.DTLVardef@1c5742f_HPS_FORMAT_FIGEXP M_FIG C_FIG TRPM2 excerbates NMDARs excitotoxicity by physically and functionally interacting with NMDARs. The disrupting pipette TAT-EE3 protects neurons against ischemic injury in vitro and in vivo.

neuroscience↗