Cited by LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies

LAG3 is not expressed in human and murine neurons and does not modulate α‐synucleinopathies DOI

et al.

EMBO Molecular Medicine, Journal Year: 2021, Volume and Issue: 13(9)

Published: July 26, 2021

Article26 July 2021Open Access Source DataTransparent process LAG3 is not expressed in human and murine neurons does modulate α-synucleinopathies Marc Emmenegger orcid.org/0000-0002-6073-8811 Institute of Neuropathology, University Zurich, Switzerland These authors contributed equally to this work Search for more papers by author Elena De Cecco orcid.org/0000-0002-0148-2596 Marian Hruska-Plochan orcid.org/0000-0002-9253-4362 Department Quantitative Biomedicine, Timo Eninger German Center Neurodegenerative Diseases (DZNE), Tübingen, Germany Cellular Neurology, Hertie Clinical Brain Research, Matthias M Schneider orcid.org/0000-0002-1894-1859 Yusuf Hamied Chemistry, Centre Misfolding Diseases, Cambridge, UK Melanie Barth Tantardini orcid.org/0000-0001-9189-3390 Pierre de Rossi Mehtap Bacioglu orcid.org/0000-0003-0304-7026 Rebekah G Langston Cell Biology Gene Expression Section, Laboratory Neurogenetics, National on Aging, Institutes Health, Bethesda, MD, USA Alice Kaganovich Nora Bengoa-Vergniory orcid.org/0000-0002-3700-0464 Physiology, Anatomy Genetics, Oxford Parkinson's Disease (OPDC), University, Oxford, Andrès Gonzalez-Guerra Merve Avar orcid.org/0000-0003-4665-5558 Daniel Heinzer orcid.org/0000-0002-3282-4042 Regina Reimann Lisa Häsler Therese W Herling Naunehal S Matharu Natalie Landeck orcid.org/0000-0002-8399-4009 Kelvin Luk orcid.org/0000-0002-6591-6269 Pathology Medicine Pennsylvania Perelman School Medicine, Philadelphia, PA, Ronald Melki orcid.org/0000-0003-0000-7096 CNRS, Institut François Jacob (MIRCen), CEA, Fontenay-aux-Roses, France Philipp J Kahle Neurodegeneration, Simone Hornemann orcid.org/0000-0002-2674-9891 Tuomas P Knowles Cavendish Laboratory, Physics, Mark R Cookson orcid.org/0000-0002-1058-3831 Magdalini Polymenidou Mathias Jucker orcid.org/0000-0001-9045-1072 Adriano Aguzzi Corresponding Author [email protected] orcid.org/0000-0002-0344-6708 Information Emmenegger1, Cecco1, Hruska-Plochan2, Eninger3,4, Schneider5, Barth3,4, Tantardini2, Rossi2, Bacioglu3,4, Langston6, Kaganovich6, Bengoa-Vergniory7, Gonzalez-Guerra1, Avar1, Heinzer1, Reimann1, Häsler3,4, Herling5, Matharu5, Landeck6, Luk8, Melki9, Kahle3,10, Hornemann1, Knowles5,11, Cookson6, Polymenidou2, Jucker3,4 *,1 1Institute 2Department 3German 4Department 5Yusuf 6Cell 7Department 8Department 9Laboratory 10Department 11Cavendish *Corresponding author. Tel: +41 44 255 21 07; E-mail: EMBO Mol Med (2021)13:e14745https://doi.org/10.15252/emmm.202114745 PDFDownload PDF article text main figures. Peer ReviewDownload a summary the editorial decision including letters, reviewer comments responses feedback. ToolsAdd favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract While initial pathology disease other often confined circumscribed brain regions, it can spread progressively affect adjacent distant locales. This may be controlled cellular receptors α-synuclein fibrils, one which was proposed immune checkpoint molecule. Here, we analysed expression pattern mouse brains. Using variety methods model systems, found no evidence neurons. confirmed that interacts with specificity interaction appears limited. Moreover, overexpression cultured neural cells did cause any worsening ex vivo. The overall survival A53T transgenic mice unaffected depletion, seeded induction lesions hippocampal slice cultures knockout. data suggest role spreading universally valid. SYNOPSIS study re-evaluated neuronal lymphocyte-activation gene 3 (LAG3) modulating α-synucleinopathies. could validated, using genomic proteomic approaches. binding fibrils appeared limited regarding its affinity. Overexpression lead an increased deposition aggregates genetic ablation prolonged expressing α-synuclein. absence influence inclusions organotypic cultures. paper explained Problem diseases are aggravating conditions tremendous impact lives affected people. Despite years concerted scientific efforts, most these remain uncurable. step causal therapies identification druggable targets interfere progression. A transmembrane protein called whose function system well established has recently been receptor disease-associated form α-synuclein, involved α-synucleinopathies, amongst them disease. Results exhaustive array vitro, vivo experiments, have unable validate We find or origin, between specificity. induce aggravation pathology, overexpressing (A53T) survival. Ultimately, depletion LAG3. Impact Our results question relevance thus, quest relevant slow down, completely abrogate, pathogenesis neurodegenerative continue unabated. Although innovative approaches needed identify therapeutic candidates, emerging need rigorously only maintain stringent record but also moderate unjustified expectations from patients stakeholders. Introduction Lymphocyte-activation inhibitory It represent target against solid haematologic tumours (Nguyen Ohashi, 2015; Andrews et al, 2017; Ascierto Lichtenegger 2018; Lim 2020; Rohatgi 2020). activated T cells, natural killer dendritic (Triebel 1990; Huard 1994, 1997; Hannier Triebel, 1999; Workman 2002, 2009; Maçon-Lemaître 2005; Camisaschi 2010), findings support system. More recently, central nervous (CNS) as pathogenic assemblies, causally (PD). Mice devoid were reported develop lower levels phosphorylated than wild-type upon inoculation pre-formed (PFFs). Furthermore, treatment anti-LAG3 antibodies attenuated pathological drastically lowered aggregation vitro (Mao 2016). finding, if confirmed, far-reaching implications. PD common movement disorder (Beitz, 2014; Deweerdt, 2016; Jankovic, 2017) causes high level suffering their families. Histologically, characterized known Lewy bodies accumulation associated neurodegeneration (Dickson, 2012; Mullin Schapira, Corbillé Substantia nigra mesencephalic regions as, some cases, amygdala neocortex 2018). Growing suggests cell (Volpicelli-Daley 2011; Volpicelli-Daley 2014), "prionoid" templated conversion (Aguzzi, Walker, Kara Henderson 2019; Karpowicz Uemura 2021). thought interrupting transmission down abrogate course. general progression prion disorders ruled out (Liu 2018), impairing still constitute attractive small drugs immunotherapy PD. systems. Additionally, studied propagation (PFFs) stem (NSC)-derived presence Finally, investigated ASYNA53T (a disease) hemizygous homozygous deletions thereof. failed detect establish Absence endogenous lines, NSC-derived samples sequence homology proteins < 70%. limit cross-species reactivity antibodies. therefore asked whether available bind extracellular domain coated 384-well microplates recombinant LAG323-450 LAG324-442 measured 8 commercially enzyme-linked immunosorbent assay (ELISA) (Fig 1A). All except LSB15026 bound exclusively LAG3, both. many epitopes differ species. Western blot analysis monoclonal antibody 4-10-C9 used Mao al (2016) either overexpressed lentivirally transduced primary cultures, whereas detected 1B). Figure 1. Binding eight commercial via indirect ELISA. Seven while (LSB15026) recognized both Specific detection blotting. No glial lines origin. band cells. lysates fully differentiated Violin plot showing RNA Identities annotate different clusters: Neuronal clusters comprised following markers: GAD2, GABRG1, NTRK2, NEFM, SNCG, SLC17A6, SCN2A, DDIT3/HRK. Mixed defined GFAP, S100B, STMN2, NRN1, GPM6B, COL1A1, astrocyte-specific COL1A1. cannot evidenced beyond few random events. Data shown 5,476 unique two independent biological replicates. Dopaminergic control glucocerebrosidase (GBA) N370S immunoblotted observed power, high-resolution laser scanning confocal microscopy, signal (Auto-hLAG3 transduced, DOX OFF) anti-human (17B4 D2G40; left panel zoomed-in insets) clearly induced express hLAG3 (DOX ON; right insets). Scale bars 25 µm. Human homogenates autopsy material homogenates. Control (tonsils cells) show expected bands. Nuclei isolated dorsolateral prefrontal cortices 16 donors, subjected snRNAseq. quantified violin plots. transcripts non-detectable all 34 distinct types, multiple excitatory neurons, oligodendrocytes (ODC), oligodendrocyte precursor (OPC) microglia (MGL), astrocytes (AST) endothelial (EC). Cluster markers detailed Saez-Atienzar 2021. online figure. 1 [emmm202114745-sup-0002-SDataFig1.zip] Download figure PowerPoint then attempted line expresses five included lymphocytes control. bands specific glial, (HEK293T) 1C). differentiation (NSC) had concomitant single-cell sequencing (scRNAseq) (Hruska-Plochan 2021), lysates. For control, additionally lentiviral plasmid encoding blotting reveal LAG3-specific non-induced 1D), scRNAseq yielded minimal counts transcript (N), mixed (MG) 1E). types comparable those T-cell checkpoints, immunoreceptor Ig ITIM domains (TIGIT) immunoglobulin mucin domain-containing (TIM3 HAVCR2) astrocytic displayed transcriptional profiles EV1A). immunoblots dopaminergic carrying polymorphism EV1B F), further suggesting Click here expand EV1. genes assessed scRNAseq. Immunofluorescence images iPSC-derived controls mutations GBA. Staining DAPI tyrosine hydroxylase (TH). bar 100 KO WT mice, controls. Anti-LAG3 used. next varies individual potentially preventing bulk methodologies such despite robust rare single performed immunofluorescence stainings Again, identified, showed obvious positivity 1G). Subsequently, areas expression. selected post-mortem frontal cortex immunoblotting. Activated lymphoepithelial tissue tonsils positive due 1H). interrogated single-nucleus (sn) RNAseq dataset described (Saez-Atienzar 2021) across types. derived neurologically healthy donors (median age 36 years, range: 16–61 male:female ratio = 1:1) clustered annotated specified saw signals above background identified clusters, 13 11 subtypes (OPC), (EC) 1I). Similar obtained examining snRNAseq datasets juvenile adult (Zhang Welch Agarwal corroborate detectable As inability contradicts previous observa

Language: Английский

Transfer learning enables predictions in network biology DOI

Christina V. Theodoris, Ling Xiao,

Anant Chopra

et al.

Nature, Journal Year: 2023, Volume and Issue: 618(7965), P. 616 - 624

Published: May 31, 2023

Language: Английский

Citations

393

Microglia in Neuroinflammation and Neurodegeneration: From Understanding to Therapy DOI

Luca Muzio, Alice Viotti, Gianvito Martino

et al.

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: Sept. 24, 2021

Microglia are the resident macrophages of central nervous system (CNS) acting as first line defense in brain by phagocytosing harmful pathogens and cellular debris. emerge from early erythromyeloid progenitors yolk sac enter developing before establishment a fully mature blood–brain barrier. In physiological conditions, during development, microglia contribute to CNS homeostasis supporting cell proliferation neural precursors. post-natal life, such cells preserving integrity neuronal circuits sculpting synapses. After injury, change their morphology down-regulate those genes homeostatic functions. However, it is still unclear whether changes accompanied molecular functional modifications that might pathological process. While comprehensive transcriptome analyses at single-cell level have identified specific gene perturbations occurring “pathological” microglia, precise protective/detrimental role neurological disorders far being elucidated. this review, results so obtained regarding neurodegenerative will be discussed. There solid sound evidence suggesting regulating functions disease pathology represent strategy develop future therapies aimed counteracting degeneration multiple sclerosis, Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis.

Language: Английский

Citations

360

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease DOI

Tushar Kamath, Abdulraouf Abdulraouf, S.J. Burris

et al.

Nature Neuroscience, Journal Year: 2022, Volume and Issue: 25(5), P. 588 - 595

Published: May 1, 2022

Abstract The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark Parkinson’s disease (PD). Nevertheless, molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed protocol to enrich and transcriptionally profile from patients PD matched controls, sampling total 387,483 nuclei, including 22,048 profiles. We identified ten populations spatially localized each SNpc using Slide-seq. A single subtype, marked by expression gene AGTR1 confined ventral tier SNpc, was highly susceptible in showed strongest upregulation targets TP53 NR2F2 , nominating processes degeneration. This same vulnerable population specifically enriched for heritable risk PD, highlighting importance cell-intrinsic determining differential PD-associated

Language: Английский

Citations

338

Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state DOI

Semra Smajić, Cesar A. Prada‐Medina, Zied Landoulsi

et al.

Brain, Journal Year: 2021, Volume and Issue: 145(3), P. 964 - 978

Published: Dec. 13, 2021

Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact aetiology remains largely unknown. To date, research has mainly focused on nigral although recent studies suggest disease-related changes also in non-neuronal cells and midbrain regions beyond substantia nigra. While there some evidence for glial involvement disease, molecular mechanisms remain poorly understood. The aim this study was to characterize contribution all cell types pathology single-nuclei RNA sequencing assess type-specific risk using latest genome-wide association study. We profiled >41 000 transcriptomes post-mortem from six idiopathic patients five age-/sex-matched controls. validate our findings spatial context, we utilized immunolabelling same tissues. Moreover, analysed disease-associated enrichment genes with expression patterns. discovered neuronal cluster CADPS2 overexpression low TH levels, which exclusively present midbrains. Validation analyses laser-microdissected neurons that represents dysfunctional neurons. With regard cells, observed an increase microglia patients. were more amoeboid, indicating activated state. reduction oligodendrocyte numbers remaining being stress-induced upregulation S100B. variants associated glia- neuron-specific gene patterns cases. Furthermore, astrocytes presented disease-specific proliferation dysregulation related unfolded protein response cytokine signalling. reactive patient showed CD44 overexpression, revealed pro-inflammatory trajectory elevated levels IL1B, GPNMB HSP90AA1. Taken together, generated first dataset midbrain, highlights as well 'pan-glial' activation central mechanism movement disorder. This finding warrants further into inflammatory signalling immunomodulatory treatments disease.

Language: Английский

Citations

333

Microglia modulate neurodegeneration in Alzheimer’s and Parkinson’s diseases DOI

Tim Bartels, Sebastiaan De Schepper, Soyon Hong

et al.

Science, Journal Year: 2020, Volume and Issue: 370(6512), P. 66 - 69

Published: Oct. 2, 2020

Dementia is a rapidly rising global health crisis that silently disables families and ends lives livelihoods around the world. To date, however, no early biomarkers or effective therapies exist. It now clear brain microglia are more than mere bystanders amyloid phagocytes; they can act as governors of neuronal function homeostasis in adult brain. Here, we highlight fundamental role tissue-resident macrophages health. Then, suggest how chronic impairment microglia-neuron cross-talk may secure permanence failure synaptic Alzheimer's Parkinson's diseases. Understanding to assess modulate interactions critical for will be key developing dementia.

Language: Английский

Citations

315

Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases DOI

Jian Sheng Loh, Wen Qi Mak, Li Tan

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Feb. 16, 2024

Abstract The human gastrointestinal tract is populated with a diverse microbial community. vast genetic and metabolic potential of the gut microbiome underpins its ubiquity in nearly every aspect biology, including health maintenance, development, aging, disease. advent new sequencing technologies culture-independent methods has allowed researchers to move beyond correlative studies toward mechanistic explorations shed light on microbiome–host interactions. Evidence unveiled bidirectional communication between central nervous system, referred as “microbiota–gut–brain axis”. microbiota–gut–brain axis represents an important regulator glial functions, making it actionable target ameliorate development progression neurodegenerative diseases. In this review, we discuss mechanisms As provides essential cues microglia, astrocytes, oligodendrocytes, examine communications microbiota these cells during healthy states Subsequently, diseases using metabolite-centric approach, while also examining role microbiota-related neurotransmitters hormones. Next, targeting intestinal barrier, blood–brain meninges, peripheral immune system counteract dysfunction neurodegeneration. Finally, conclude by assessing pre-clinical clinical evidence probiotics, prebiotics, fecal transplantation A thorough comprehension will foster effective therapeutic interventions for management

Language: Английский

Citations

255

The Contribution of Microglia to Neuroinflammation in Parkinson’s Disease DOI

Katja Badanjak, Sonja Fixemer, Semra Smajić

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(9), P. 4676 - 4676

Published: April 28, 2021

With the world’s population ageing, incidence of Parkinson’s disease (PD) is on rise. In recent years, inflammatory processes have emerged as prominent contributors to pathology PD. There great evidence that microglia a significant neuroprotective role, and impaired over activated microglial phenotypes are present in brains PD patients. Thereby, progression potentially driven by vicious cycle between dying neurons through instigation oxidative stress, mitophagy autophagy dysfunctions, a-synuclein accumulation, pro-inflammatory cytokine release. Hence, investigating involvement importance for future research treatment The purpose this review highlight findings concerning microglia-neuronal interplay with focus human postmortem immunohistochemistry single-cell studies, their relation animal iPSC-derived models, newly emerging technologies, resulting potential new anti-inflammatory therapies

Language: Английский

Citations

198

Ferroptosis in Parkinson’s disease: glia–neuron crosstalk DOI

Zhangli Wang, Lin Yuan, Wen Li

et al.

Trends in Molecular Medicine, Journal Year: 2022, Volume and Issue: 28(4), P. 258 - 269

Published: March 7, 2022

Iron uptake, storage, efflux, and utilization are essential for maintaining iron homeostasis. Abnormal expression of proteins involved in these processes related to homeostasis may cause overload induce subsequent ferroptosis, which is associated with the pathogenesis neurodegenerative disease.Crosstalk between glia neurons underlies ferroptotic alterations DA form a vicious circle promoting PD pathogenesis.Possible mechanisms transfer include exosomes tunneling nanotubes. They determine efficacy ferroptosis inhibitors provide clue exploring novel therapeutic interventions PD.Joint medications anti-inflammatory medicines potential strategy treatment diseases. Parkinson's disease (PD) characterized by dopaminergic (DA) neuron loss formation cytoplasmic protein inclusions. Although exact unknown, dyshomeostasis has been proposed as contributing factor. Emerging evidence suggests that glial cell activation plays pivotal role neurodegeneration. We review association deposition, activation, neuronal death, discuss whether how affects α-synuclein aggregation loss. examine possible roles different types mediating neurons. Lastly, we current clinical trials targeting already evaluating modulation PD, much remains unknown about metal ion metabolism regulation pathogenesis. one most common Two major pathological hallmarks progressive substantia nigra pars compacta (SNpc) Lewy bodies neurites. Misfolded aggregated (α-syn; see Glossary) primary component pathology [1.Jankovic J. et al.Parkinson's disease: etiopathogenesis treatment.J. Neurol. Neurosurg. Psychiatry. 2020; 91: 795-808Crossref PubMed Scopus (98) Google Scholar]. To date, relatively little known pathogenesis, although immune mitochondrial dysfunction, lipid dyshomeostasis, imbalance Notably, evident during onset progression [2.Kam T.I. al.Microglia astrocyte dysfunction disease.Neurobiol. Dis. 144105028Crossref (55) Activated act 'double-edged swords' because they can exert neuroprotective effects releasing neurotrophic factors phagocytosis, while damage proinflammatory cytokines [3.Liddelow S.A. al.Neurotoxic reactive astrocytes induced activated microglia.Nature. 2017; 541: 481-487Crossref (2734) Brain imaging studies have shown correlations deposition SNpc patient brains [4.Depierreux F. multimodal imaging: F-DOPA PET, neuromelanin-sensitive quantitative iron-sensitive MRI.NPJ 2021; 7: 57Crossref (2) Scholar,5.Biondetti E. al.The spatiotemporal changes dopamine, neuromelanin characterizing disease.Brain. 144: 3114-3125Crossref (5) Scholar], indicating be factor closely death PD. This type iron-dependent termed [6.Dixon S.J. al.Ferroptosis: an nonapoptotic death.Cell. 2012; 149: 1060-1072Abstract Full Text PDF (3929) Excessive accumulation cultured cells trigger [7.Zhang P. al.Ferroptosis was more initial caused its underlying mechanism disease.Free Radic. Biol. Med. 152: 227-234Crossref (41) Ferroptosis also reported SH-SY5Y (human neuroblastoma) exposed neurotoxins, 1-methyl-4-phenylpyridinium (MPP+) 6-hydroxydopamine (6-OHDA) [8.Sun Y. al.Activation p62–Keap1–Nrf2 pathway protects 6-hydroxydopamine-induced cells.Mol. Neurobiol. 57: 4628-4641Crossref (27) Scholar,9.Ito K. al.MPP+ induces necrostatin-1- ferrostatin-1-sensitive necrotic cells.Cell Death Discov. 3: 17013Crossref (51) Similar phenomena were observed MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced mouse models [10.Do Van B. al.Ferroptosis, newly regulated PKC.Neurobiol. 2016; 94: 169-178Crossref (266) Furthermore, rescue Both crucial events reciprocally influence each other 'partners crime' boosting degeneration [11.Fernández-Mendívil C. al.Protective microglial HO-1 blockade aging: implication metabolism.Redox 38101789Crossref (21) Scholar,12.Zhu al.Iron microglia contribute hyperechogenicity 6-OHDA-induced rat model disease.Parkinsonism Relat. Disord. 36: 76-82Abstract (24) promote aggravates [13.Novgorodov al.Acid sphingomyelinase promotes due glutamate-induced necrosis.J. Lipid Res. 2018; 59: 312-329Abstract (34) These findings suggest deposition-induced neurodegeneration could potentially underlie address regulatory neurons, especially glia, focus on involvement first process particular their impact pathologies. regulate oxidative stress modulate ferroptosis. recent ongoing leverage initiated abnormal severe peroxidation, leading Unlike apoptosis forms ferroptosis-induced cytological volume shrinkage disappearance mitochondria cristae, increased membrane density, outer rupture Scholar,14.Friedmann Angeli J.P. al.Inactivation regulator Gpx4 triggers acute renal failure mice.Nat. Cell 2014; 16: 1180-1191Crossref (1148) However, nuclei maintain structural integrity, there no or organelle swelling, plasma rupture, apoptotic probably multiple pathways, including metabolism, stress, cytotoxic amino acid (Figure 1). In addition, susceptibility affected pathways such suppressor 1 (FSP1)–coenzyme Q10 (CoQ10) [15.Bersuker CoQ oxidoreductase FSP1 acts parallel GPX4 inhibit ferroptosis.Nature. 2019; 575: 688-692Crossref (627) remain obscure, participation non-neuronal toxicity Several demonstrated regulating For example, it heme oxygenase (HO-1), inducible enzyme, catabolizes group into carbon monoxide biliverdin, turn converts bilirubin labile iron. aging wild-type mice, upregulated accompanied By contrast, cell-specific knockout Hmox1 gene mice chelator deferoxamine (DFX) showed preventive against cancer found mutations genes linked (Table 1), DJ-1, autosomal recessive gene, encodes negative modulator [16.Cao al.DJ-1 suppresses through preserving activity S-adenosyl homocysteine hydrolase.Nat. Commun. 11: 1251Crossref (50) Moreover, characteristics induction highly consistent patients, content peroxidation [17.Sun W.Y. al.Phospholipase iPLA(2)β averts eliminating redox signal.Nat. 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Sci. 20: 771Crossref (12) defects system decreased cystine/glutamate antiporter (xCT) [20.Vallerga C.L. al.Analysis DNA methylation associates cystine-glutamate SLC7A11 risk disease.Nat. 1238Crossref glutathione (GSH) [21.Venkateshappa al.Increased function human compared striatum: implications disease.Neurochem. 37: 358-369Crossref (111) DJ-1 (that maintains cysteine GSH biosynthesis) CoQ10 [22.Mischley L.K. al.Coenzyme deficiency patients disease.J. 318: 72-75Abstract (59) cellular animal treated MPP+ 6-OHDA, MPTP-lesioned 9.Ito 10.Do inhibition using ferrostatin-1 (Fer-1) alleviate locomotor behavioral deficits tyrosine hydroxylase (TH) MPTP-induced [23.Bai L. al.Thioredoxin-1 rescues MPP+/MPTP-induced increasing peroxidase 4.Mol. 58: 3187-3197Crossref (6) A very study combined MRI imaging, mapping (QSM), regional profiling cohort (96) 35 control subjects significantly cortical subjects. Gene heavy detoxification synaptic predominantly differentially expressed glutamatergic [24.Thomas G.E.C. al.Regional brain insights 1787-1798Crossref (7) suggesting selective vulnerabilities relation this prominent lead largely unknown. Further studies, particularly biological urgently needed.Table 1Ferroptosis-related PDaAbbreviations: FTH1, ferritin chain 1; IL-13, interleukin-13; IL-13Rα1, interleukin-13 receptor α1; iPLA2β, Ca2+-independent phospholipase A2β (encoded PLA2G6/PNPLA9); SLC7A11, solute carrier family 7 member 11; SNX5, sorting nexin 5; Trx-1, thioredoxin-1.GeneFunctionRefsACSL4ACSL4 free fatty acids fatty-CoA esters[69.Song L.M. al.Apoferritin improves motor MPTP-treated ferroptosis.iScience. 24: 102431Abstract Scholar]DJ1DJ-1 biosynthesis trans-sulfuration pathway[16.Cao Scholar,92.Jiang C terminus determines homodimerization, MGO suppression ferroptosis.Acta Pharmacol. Sin. 42: 1150-1159Crossref Scholar]FTH1FTH1 inhibits ferritinophagy 6-OHDA PD[93.Tian al.FTH1 Inhibits disease.Neurotherapeutics. 1796-1812Crossref (37) Scholar]GPX4GPX4 reduces phospholipid hydroperoxides ferroptosis[10.Do Scholar,94.Hambright W.S. al.Ablation 4 forebrain cognitive neurodegeneration.Redox 12: 8-17Crossref (300) Scholar]IL13,IL13RA1The interaction IL-13 IL-13Rα1 increases stress[95.Aguirre C.A. al.Two single nucleotide polymorphisms IL13 IL13RA1 individuals idiopathic increase stress.Brain Behav. Immun. 88: 920-924Crossref (3) Scholar]PLA2G6Phospholipase iPLA2β signal[17.Sun Scholar]miR-335miR-335 enhances degradation FTH1[96.Li X. al.miR-335 vivo vitro disease.Int. 47: 61Crossref Scholar]NRF2Nrf2 directly indirectly modulating GSH, iron, lipids, well function[72.Ishii T. al.Circadian BDNF-mediated Nrf2 ferroptosis.Free 133: (62) Scholar]TP53Inhibition p53 upregulates GPX4[97.Li S. al.p53-mediated required 1-methyl-4-phenylpyridinium-induced senescence PC12 cells.Toxicol. Vitro. 73105146Crossref Scholar]SQSTM1High p62 nuclear upregulating expression[8.Sun Scholar]SLC7A11Codes xCT regulates levels[20.Vallerga Scholar]SNX5Silencing SNX5 lowers level cells[98.Si W. al.Super-enhancer-driven 5 models.Biochem. Biophys. 567: 35-41Crossref Scholar]Trx1Trx-1 overexpression decrease ROS[23.Bai Scholar]a Abbreviations: thioredoxin-1. Open table tab α-Syn key feature Different α-syn spread another peripheral tissues within [25.Liu D. al.Differential seeding propagating efficiency strains generated conditions.Transl. Neurodegener. 10: 20Crossref 26.Hansen al.α-Synuclein propagates grafted seeds cells.J. Clin. Invest. 2011; 121: 715-725Crossref (604) 27.Luk K.C. al.Pathological transmission initiates Parkinson-like nontransgenic mice.Science. 338: 949-953Crossref (1446) Postmortem analyses coexistence midbrain [28.Castellani R.J. al.Sequestration disease.Acta Neuropathol. 2000; 100: 111-114Crossref (191) accumulates substantial colocalizes [29.Ayton al.Nigral elevation invariable sufficient neurodegeneration.Biomed. Int. 2014581256Crossref (97) Scholar,30.Guo J.J. al.Intranasal administration preformed fibrils Macaca fascicularis.Cell 81Crossref (8) pathology. metal-binding affinity ferric ferrous binding inducing conformational [31.Golts N. al.Magnesium spontaneous iron-induced alpha-synuclein.J. 2002; 277: 16116-16123Abstract (162) takes part post-transcriptional [32.Febbraro modulated at translational iron.Neuroreport. 23: 576-580Crossref (77) Scholar] post-translational modification [33.Wang R. al.Iron-induced contributes phosphorylation up-regulation via polo-like kinase 2 casein 2.Neurochem. 125: 127-135Crossref mRNA contains response element (IRE) 5′-untranslated region (UTR) [34.Friedlich A.L. alpha-synuclein messengerRNA predicted responsive element.Mol. 2007; 222-223Crossref (134) N2A (mouse cells, addition ions accelerate spreading aggregation. The aggregates formed cytotoxic, oxygen species (ROS) production [35.Li al.Copper prion-like propagation α-synuclein: cycle Macromol. 163: 562-573Crossref (15) depletion HEK293 leads reduced translation adeno-associated virus (AAV) α-syn-overexpression model, chronic intranasal (DFO) reduce [36.Febbraro al.Chronic ameliorates rAAV model.Exp. 2013; 247: 45-58Crossref (40) Intranasal DFO improve memory healthy [37.Fine J.M. C57 partially non-disease-specific functional neurologic improvement.Brain 10e01536Crossref data indicate play death. Conversely, Overexpression results [38.Ortega over-expression redistribution iron-exposed neurons.Mol. 53: 1925-1934Crossref ferrireductase intracellular [39.Davies al.Alpha-synuclein ferrireductase.PLoS One. 6e15814Crossref prevent membranes pluripotent stem (iPSC)-derived triplication SNCA led radicals further prevented [40.Angelova P.R. al.Alpha synuclein drives ferroptosis: interplay calcium peroxidation.Cell Differ. 27: 2781-2796Crossref (44) Evidence obtained close turnover, expression, accumulation, aggregation, degradation. causal relationship two unclear. still insufficient, considering pathology, normal potential. Glial various 2). Large numbers around degenerated SN [41.Imamura al.Distribution histocompatibility complex class II-positive cytokine profile brains.Acta 2003; 106: 518-526Crossref (480) Reactive detected autopsies brains, inclusions [42.Braak H. al.Development immunoreactive parallels stages intraneuronal sporadic 114: 231-241Crossref (261) factors, nitric oxide (NO), ROS, glutamate Scholar,43.Subhramanyam C.S. al.Microglia-mediated neuroinflammation diseases.Semin. Dev. 112-120Crossref (206) PD-associated leucine-rich repeat (LRRK2) oligodendrocytes, precursor (OPCs) [44.Agarwal al.A single-cell atlas reveals neurological disorders.Nat. 4183Crossref Scholar,45.Bryois al.Genetic identification traits yields etiology Genet. 52: 482-493Crossref (74) demyelination release. Upon disrupting homeostasis, altering stress. Studies networks. First, accumulate microglia, resulting central nervous (CNS) [30.Guo Scholar,46.Kenkhuis loading Alzheimer's patients.Act

Language: Английский

Citations

186

Specialized astrocytes mediate glutamatergic gliotransmission in the CNS DOI

Roberta De Ceglia, Ada Ledonne, David Litvin

et al.

Nature, Journal Year: 2023, Volume and Issue: 622(7981), P. 120 - 129

Published: Sept. 6, 2023

Abstract Multimodal astrocyte–neuron communications govern brain circuitry assembly and function 1 . For example, through rapid glutamate release, astrocytes can control excitability, plasticity synchronous activity 2,3 of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions 4–7 communicate fast focal they should possess an apparatus for Ca 2+ -dependent exocytosis similar neurons 8–10 However, the existence this mechanism has been questioned 11–13 owing inconsistent data 14–17 a lack direct supporting evidence. Here we revisited astrocyte hypothesis by considering emerging molecular heterogeneity 18–21 using molecular, bioinformatic imaging approaches, together with cell-specific genetic tools that interfere vivo. By analysing existing single-cell RNA-sequencing databases our patch-seq data, identified nine molecularly distinct clusters hippocampal astrocytes, among which found notable subpopulation selectively expressed synaptic-like glutamate-release machinery localized discrete sites. Using GluSnFR-based 22 situ vivo, corresponding subgroup responds reliably astrocyte-selective stimulations subsecond release events at spatially precise hotspots, were suppressed astrocyte-targeted deletion vesicular transporter (VGLUT1). Furthermore, or its isoform VGLUT2 revealed specific contributions glutamatergic cortico-hippocampal nigrostriatal circuits during normal behaviour pathological processes. uncovering atypical specialized adult brain, provide insights into complex roles central nervous system (CNS) physiology diseases, identify potential therapeutic target.

Language: Английский

Citations

150

Single-cell atlases: shared and tissue-specific cell types across human organs DOI

Rasa Elmentaite, Cecilia Domínguez Conde, Lu Yang

et al.

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 23(7), P. 395 - 410

Published: Feb. 25, 2022

Language: Английский

Citations

131