ArticleNature communications2024
Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 27 papers.
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27 citing papers in PubMed.
- Deletion or immunotherapeutic blockade of FcγRIIb (CD32b) impairs α-Syn propagation in vivo.Acta neuropathologica · 2026Article
- Galectin-9 activates microglial asparagine endopeptidase and promotes α-synuclein pathology in Parkinson's disease.Cell death and differentiation · 2026Article
- Engineered neuronal exosomes mediate α-synuclein clearance to ameliorate Parkinson's disease.Journal of nanobiotechnology · 2026Article
- Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.Translational neurodegeneration · 2026Review
- "Unfolding Parkinson's Disease Through the Microbiome-Gut-Brain Axis".Journal of molecular neuroscience : MN · 2026Review
- PD-1, BTLA and TIGIT as therapeutic targets for rheumatic disease.Nature reviews. Rheumatology · 2026Review
- Activating protein kinases to treat diseases: Current understanding and future challenges.Acta pharmaceutica Sinica. B · 2026Review
- Discovery of Abundant Nano-scale Lymphatic-like Vessels in Brains.bioRxiv : the preprint server for biology · 2026Article
- Microglial Lag3 Drives α-Synuclein-induced Neurotoxic Activated (A1) Astrocytes and Neurodegeneration.bioRxiv : the preprint server for biology · 2026Article
- Propagation of α-synuclein pathology: models, mechanisms and future goals.Molecular neurodegeneration advances · 2026Review
- Research progress on the α-synuclein-lysosome axis in Parkinson's disease: molecular mechanisms of protein aggregation, autophagy dysfunction, and therapeutic targeting.Frontiers in neuroscience · 2026Review
- Targeted α-Synuclein mRNA Degradation by PMO-Based RNA-Degrading Chimeras.bioRxiv : the preprint server for biology · 2025Article
- Lewy body dementia promotion by air pollutants.Science (New York, N.Y.) · 2025Article
- A New Driver of Parkinson's Disease: FAM171A2 Facilitates α-Synuclein Uptake and Spread.Neuroscience bulletin · 2025Article
- Establishment of a novel alloxan-induced rabbit model exhibiting unique diabetic retinal neuropathy features assessed via ERG + VEP.Animal models and experimental medicine · 2025Article
- Design of Ig-like binders targeting α-synuclein fibril for mitigating its pathological activities.Nature communications · 2025Article
- TREM2 and LAG-3 in cancer and Alzheimer's disease immunotherapy.Trends in pharmacological sciences · 2025Review
- LAG3 limits regulatory T cell proliferation in α-synuclein gut-to-brain transmission model.Journal of neuroinflammation · 2025Article
- LAG Time in the Era of Immunotherapy-New Molecular Insights Into the Immunosuppression Mechanism of Lymphocyte Activation Gene-3.Immunological reviews · 2025Review
- Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions.Molecular neurodegeneration · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
42 authors.
Xiaobo Mao *Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. xmao4@jhmi.edu.ORCID http://orcid.org/0000-0001-6587-556X
Hao Gu *Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Donghoon Kim *Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0002-7493-0935
Yasuyoshi KimuraNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0001-9147-8058
Ning WangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0002-3410-8509
Enquan XuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0003-3463-0337
Ramhari KumbharNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Xiaotian MingNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Haibo WangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0002-7549-5613
Chan ChenNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0001-5823-8247
Shengnan ZhangInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai, 201210, China.
Chunyu JiaInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai, 201210, China.
Yuqing LiuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0002-7566-8529
Hetao BianNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Senthilkumar S KaruppagounderNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Fatih AkkentliNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Qi ChenNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Longgang JiaNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Heehong HwangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Su Hyun LeeNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Xiyu KeInstitute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD, 21218, USA.
Michael ChangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0003-4719-0262
Amanda LiNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jun YangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0001-5908-5123
Cyrus RastegarNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Manjari SriparnaNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0003-3272-7370
Preston GeNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0001-7933-0843
Saurav BrahmachariNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0009-0004-3056-6213
Sangjune KimNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0003-3052-3163
Shu ZhangNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.ORCID http://orcid.org/0000-0001-6816-0172
Yasushi ShimodaDepartment of Bioengineering, Nagaoka University of Technology, 1603-1 Kamitomiokamachi, Nagaoka, Niigata, 940-2188, Japan.ORCID http://orcid.org/0000-0001-9230-6784
Martina SaarInstitute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.
Haiqing LiuNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Sin Ho KweonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Mingyao YingDepartment of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Creg J WorkmanDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.ORCID http://orcid.org/0000-0002-9964-9509
Dario A A VignaliDepartment of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15261, USA.ORCID http://orcid.org/0000-0002-2771-5992
Ulrike C MullerInstitute for Pharmacy and Molecular Biotechnology IPMB, Department of Functional Genomics, University of Heidelberg, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany.ORCID http://orcid.org/0000-0002-0587-2575
Cong LiuInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 26 Qiuyue Road, Shanghai, 201210, China.ORCID http://orcid.org/0000-0003-3425-6672
Han Seok KoNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. hko3@jhmi.edu.ORCID http://orcid.org/0000-0002-0864-5239
Valina L DawsonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. vdawson1@jhmi.edu.ORCID http://orcid.org/0000-0002-2915-3970
Ted M DawsonNeuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. tdawson@jhmi.edu.ORCID http://orcid.org/0000-0002-6459-0893
Funding
Synergies among inhibitory receptors in tolerance, cancer & antiviral immunityP01AI108545 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Arlene H. Sharpe · 2015 to 2026
$30.8MMedical Scientist Training ProgramT32GM144273 · NIGMS · HARVARD MEDICAL SCHOOL · PI David Shumway Jones, Jacqueline A. Lees · 2022 to 2026
$14.7MMurine Mutagenesis CoreP30NS050274 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KOLODKIN, ALEX L · 2005 to 2020
$10.9MStructure, Function and Mechanistic Analysis of LAG3R01AI144422 · NIAID · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Roy A Mariuzza, Dario AA Vignali · 2019 to 2026
$5.9MMechanism of Pathologic Tau Fibrils Neuron-to-Neuron Transmission and Neuroinflammation in Alzheimer's DiseaseR01AG073291 · NIA · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO · 2021 to 2025
$3.2MHeterochronic Blood Exchange Inhibits α?Synucleinopathy through Modulating Plasma Protein's Mediation on Pathological α?Synuclein SpreadingR01AG071820 · NIA · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO · 2021 to 2025
$2.3Mα-Synuclein strain properties are associated with diagnosis of and progression to Parkinson's disease with dementiaRF1NS125592 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO, ROSENTHAL, LIANA ISA SHAPIRO · 2022 to 2022
$2.1MUnderstanding the Mechanism of Pathological alpha-Synuclein TransmissionR01NS107318 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO · 2019 to 2023
$2.0MThe role of NOD2/RIPK2 signaling in the pathogenesis of Parkinson's DiseaseR01NS107404 · NINDS · JOHNS HOPKINS UNIVERSITY · PI KO, HANSEOK · 2018 to 2022
$1.8MInfluence of Aging on Pathogenic Alpha-Synuclein Strains and Transmission MechanismK01AG056841 · NIA · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO · 2017 to 2021
$651kChemical Fingerprints of Cognitive Impairment-related alpha-Synuclein Strains using 3D Small Molecule Microarray and Related Therapeutic ApplicationR21NS125559 · NINDS · JOHNS HOPKINS UNIVERSITY · PI MAO, XIAOBO · 2022 to 2022
$450kAdrienne Helis Malvin Medical Research Foundation M2014American Parkinson Disease Association (American Parkinson Disease Association, Inc.) n/aAmerican Parkinson Disease Association (American Parkinson Disease Association, Inc.) PDF-APDA-SFW-1650JPB Foundation n/aMaryland Stem Cell Research Fund (MSCRF) 2019-MSCRFD-4292Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation) 020608NIAID NIH HHS P01 AI108545NIAID NIH HHS R01 AI144422NIA NIH HHS K01 AG056841NIA NIH HHS R01 AG071820NIA NIH HHS R01 AG073291NIGMS NIH HHS T32 GM144273NINDS NIH HHS P30 NS050274NINDS NIH HHS R01 NS107318NINDS NIH HHS R01 NS107404NINDS NIH HHS R21 NS125559NINDS NIH HHS RF1 NS125592Parkinson's Disease Foundation (Parkinson's Disease Foundation, Inc.) PDF-SFW-1572Uehara Memorial Foundation n/aU.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI108545U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (NIAID) AI144422U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS107318U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS107404U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) NS125559U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG056841U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG071820U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging) AG073291
Abstract
Pathologic α-synuclein (α-syn) spreads from cell-to-cell, in part, through binding to the lymphocyte-activation gene 3 (Lag3). Here we report that amyloid β precursor-like protein 1 (Aplp1) interacts with Lag3 that facilitates the binding, internalization, transmission, and toxicity of pathologic α-syn. Deletion of both Aplp1 and Lag3 eliminates the loss of dopaminergic neurons and the accompanying behavioral deficits induced by α-syn preformed fibrils (PFF). Anti-Lag3 prevents the internalization of α-syn PFF by disrupting the interaction of Aplp1 and Lag3, and blocks the neurodegeneration induced by α-syn PFF in vivo. The identification of Aplp1 and the interplay with Lag3 for α-syn PFF induced pathology deepens our insight about molecular mechanisms of cell-to-cell transmission of pathologic α-syn and provides additional targets for therapeutic strategies aimed at preventing neurodegeneration in Parkinson's disease and related α-synucleinopathies.
Indexed as
alpha-SynucleinLymphocyte Activation Gene 3 ProteinAmyloid beta-Protein PrecursorAnimalsAntigens, CDDopaminergic NeuronsFemaleHumansMaleMiceMice, Inbred C57BLMice, KnockoutParkinson DiseaseProtein Bindingalpha-SynucleinAmyloid beta-Protein PrecursorAntigens, CDAPLP1 protein, humanLag3 protein, humanLymphocyte Activation Gene 3 Protein
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