TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration.
Journal
Nature neuroscience
ISSN: 1546-1726
Titre abrégé: Nat Neurosci
Pays: United States
ID NLM: 9809671
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
21
12
2020
accepted:
02
11
2021
pubmed:
18
12
2021
medline:
7
4
2022
entrez:
17
12
2021
Statut:
ppublish
Résumé
Triggering receptor expressed on myeloid cell 2 (TREM2) is linked to risk of neurodegenerative disease. However, the function of TREM2 in neurodegeneration is still not fully understood. Here, we investigated the role of microglial TREM2 in TAR DNA-binding protein 43 (TDP-43)-related neurodegeneration using virus-mediated and transgenic mouse models. We found that TREM2 deficiency impaired phagocytic clearance of pathological TDP-43 by microglia and enhanced neuronal damage and motor impairments. Mass cytometry analysis revealed that human TDP-43 (hTDP-43) induced a TREM2-dependent subpopulation of microglia with high CD11c expression and phagocytic ability. Using mass spectrometry (MS) and surface plasmon resonance (SPR) analysis, we further demonstrated an interaction between TDP-43 and TREM2 in vitro and in vivo as well as in human tissues from individuals with amyotrophic lateral sclerosis (ALS). We computationally identified regions within hTDP-43 that interact with TREM2. Our data highlight that TDP-43 is a possible ligand for microglial TREM2 and that this interaction mediates neuroprotection of microglia in TDP-43-related neurodegeneration.
Identifiants
pubmed: 34916658
doi: 10.1038/s41593-021-00975-6
pii: 10.1038/s41593-021-00975-6
pmc: PMC8741737
mid: NIHMS1753734
doi:
Substances chimiques
DNA-Binding Proteins
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
TDP-43 protein, mouse
0
Trem2 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
26-38Subventions
Organisme : NINDS NIH HHS
ID : R01 NS110949
Pays : United States
Organisme : NIA NIH HHS
ID : U19 AG069701
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG066395
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG064159
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS088627
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018).
pubmed: 30258234
pmcid: 6817969
doi: 10.1038/s41593-018-0242-x
Ulland, T. K. & Colonna, M. TREM2—a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018).
pubmed: 30266932
doi: 10.1038/s41582-018-0072-1
Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013).
pubmed: 23150934
doi: 10.1056/NEJMoa1211851
Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013).
pubmed: 23150908
doi: 10.1056/NEJMoa1211103
Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015).
pubmed: 25728668
pmcid: 4477963
doi: 10.1016/j.cell.2015.01.049
Zhao, Y. et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97, 1023–1031 (2018).
pubmed: 29518356
pmcid: 5889092
doi: 10.1016/j.neuron.2018.01.031
Ou, S. H., Wu, F., Harrich, D., Garcia-Martinez, L. F. & Gaynor, R. B. Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs. J. Virol. 69, 3584–3596 (1995).
pubmed: 7745706
pmcid: 189073
doi: 10.1128/jvi.69.6.3584-3596.1995
Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006).
pubmed: 17023659
doi: 10.1126/science.1134108
Cairns, N. J. et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227–240 (2007).
pubmed: 17591968
pmcid: 1941578
doi: 10.2353/ajpath.2007.070182
Cady, J. et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 71, 449–453 (2014).
pubmed: 24535663
pmcid: 4087113
doi: 10.1001/jamaneurol.2013.6237
Rayaprolu, S. et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease. Mol. Neurodegener. 8, 19 (2013).
pubmed: 23800361
pmcid: 3691612
doi: 10.1186/1750-1326-8-19
Krasemann, S. et al. The TREM2–APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017).
pubmed: 28930663
pmcid: 5719893
doi: 10.1016/j.immuni.2017.08.008
Maniatis, S. et al. Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364, 89–93 (2019).
pubmed: 30948552
doi: 10.1126/science.aav9776
Walker, A. K. et al. Functional recovery in new mouse models of ALS/FTLD after clearance of pathological cytoplasmic TDP-43. Acta Neuropathol. 130, 643–660 (2015).
pubmed: 26197969
pmcid: 5127391
doi: 10.1007/s00401-015-1460-x
Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201 (2010).
pubmed: 20234358
doi: 10.1038/nrneurol.2010.17
Mrdjen, D. et al. High-dimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48, 380–395 (2018).
pubmed: 29426702
doi: 10.1016/j.immuni.2018.01.011
Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017).
pubmed: 28602351
doi: 10.1016/j.cell.2017.05.018
Eyo, U. B. et al. P2Y12R-dependent translocation mechanisms gate the changing microglial landscape. Cell Rep. 23, 959–966 (2018).
pubmed: 29694903
pmcid: 5965271
doi: 10.1016/j.celrep.2018.04.001
Spiller, K. J. et al. Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy. Nat. Neurosci. 21, 329–340 (2018).
pubmed: 29463850
pmcid: 5857237
doi: 10.1038/s41593-018-0083-7
Steinacker, P. et al. TDP-43 in cerebrospinal fluid of patients with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch. Neurol. 65, 1481–1487 (2008).
pubmed: 19001167
pmcid: 2690860
doi: 10.1001/archneur.65.11.1481
Zhong, J. et al. The interactome of a PTB domain-containing adapter protein, Odin, revealed by SILAC. J. Proteom. 74, 294–303 (2011).
doi: 10.1016/j.jprot.2010.11.006
Guenther, E. L. et al. Atomic structures of TDP-43 LCD segments and insights into reversible or pathogenic aggregation. Nat. Struct. Mol. Biol. 25, 463–471 (2018).
pubmed: 29786080
pmcid: 5990464
doi: 10.1038/s41594-018-0064-2
Lee, E. B., Lee, V. M. & Trojanowski, J. Q. Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat. Rev. Neurosci. 13, 38–50 (2011).
pubmed: 22127299
pmcid: 3285250
doi: 10.1038/nrn3121
Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223 (2019).
pubmed: 30606613
doi: 10.1016/j.neuron.2018.12.006
Liu, Y. U. et al. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat. Neurosci. 22, 1771–1781 (2019).
pubmed: 31636449
pmcid: 6858573
doi: 10.1038/s41593-019-0511-3
Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019).
pubmed: 30617257
pmcid: 6417433
doi: 10.1038/s41593-018-0296-9
Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019).
pubmed: 31235932
pmcid: 6660358
doi: 10.1038/s41593-019-0433-0
Lee, C. Y. D. et al. Elevated TREM2 gene dosage reprograms microglia responsivity and ameliorates pathological phenotypes in Alzheimer’s disease models. Neuron 97, 1032–1048 (2018).
pubmed: 29518357
pmcid: 5927822
doi: 10.1016/j.neuron.2018.02.002
Konishi, H. & Kiyama, H. Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases. Front. Cell. Neurosci. 12, 206 (2018).
pubmed: 30127720
pmcid: 6087757
doi: 10.3389/fncel.2018.00206
Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017).
pubmed: 28483841
pmcid: 5494532
doi: 10.15252/embr.201743922
Zheng, H. et al. TREM2 promotes microglial survival by activating Wnt/β-catenin pathway. J. Neurosci. 37, 1772–1784 (2017).
pubmed: 28077724
pmcid: 5320608
doi: 10.1523/JNEUROSCI.2459-16.2017
Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016).
pubmed: 26642091
doi: 10.1038/nn.4189
Gu, N. et al. Spinal microgliosis due to resident microglial proliferation is required for pain hypersensitivity after peripheral nerve injury. Cell Rep. 16, 605–614 (2016).
pubmed: 27373153
pmcid: 4956495
doi: 10.1016/j.celrep.2016.06.018
Otero, K. et al. Macrophage colony-stimulating factor induces the proliferation and survival of macrophages via a pathway involving DAP12 and β-catenin. Nat. Immunol. 10, 734–743 (2009).
pubmed: 19503107
pmcid: 4004764
doi: 10.1038/ni.1744
Brown, G. C. & Neher, J. J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014).
pubmed: 24646669
doi: 10.1038/nrn3710
Fu, R., Shen, Q., Xu, P., Luo, J. J. & Tang, Y. Phagocytosis of microglia in the central nervous system diseases. Mol. Neurobiol. 49, 1422–1434 (2014).
pubmed: 24395130
pmcid: 4012154
doi: 10.1007/s12035-013-8620-6
Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016).
pubmed: 27033548
pmcid: 5094372
doi: 10.1126/science.aad8373
Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007).
pubmed: 17410128
pmcid: 3464483
doi: 10.1038/nature05704
Tufail, Y. et al. Phosphatidylserine exposure controls viral innate immune responses by microglia. Neuron 93, 574–586 e578 (2017).
pubmed: 28111081
pmcid: 5600182
doi: 10.1016/j.neuron.2016.12.021
Das, R. & Chinnathambi, S. Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell. Mol. Life Sci. 76, 3681–3694 (2019).
pubmed: 31093687
doi: 10.1007/s00018-019-03132-2
Harms, A. S. et al. MHCII is required for α-synuclein-induced activation of microglia, CD4 T cell proliferation, and dopaminergic neurodegeneration. J. Neurosci. 33, 9592–9600 (2013).
pubmed: 23739956
pmcid: 3903980
doi: 10.1523/JNEUROSCI.5610-12.2013
Bulloch, K. et al. CD11c/EYFP transgene illuminates a discrete network of dendritic cells within the embryonic, neonatal, adult, and injured mouse brain. J. Comp. Neurol. 508, 687–710 (2008).
pubmed: 18386786
doi: 10.1002/cne.21668
Sheean, R. K. et al. Association of regulatory T-cell expansion with progression of amyotrophic lateral sclerosis: a study of humans and a transgenic mouse model. JAMA Neurol. 75, 681–689 (2018).
pubmed: 29507931
pmcid: 5885208
doi: 10.1001/jamaneurol.2018.0035
Sato-Hashimoto, M. et al. Microglial SIRPα regulates the emergence of CD11c
doi: 10.7554/eLife.42025
Atagi, Y. et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290, 26043–26050 (2015).
pubmed: 26374899
pmcid: 4646257
doi: 10.1074/jbc.M115.679043
Feiler, M. S. et al. TDP-43 is intercellularly transmitted across axon terminals. J. Cell Biol. 211, 897–911 (2015).
pubmed: 26598621
pmcid: 4657165
doi: 10.1083/jcb.201504057
Zhong, L. et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat. Commun. 10, 1365 (2019).
pubmed: 30911003
pmcid: 6433910
doi: 10.1038/s41467-019-09118-9
Kober, D. L. et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife 5, e20391 (2016).
pubmed: 27995897
pmcid: 5173322
doi: 10.7554/eLife.20391
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C. & Sheng, M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-β by microglia. Neuron 91, 328–340 (2016).
pubmed: 27477018
doi: 10.1016/j.neuron.2016.06.015
Ling, J. P., Pletnikova, O., Troncoso, J. C. & Wong, P. C. TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD. Science 349, 650–655 (2015).
pubmed: 26250685
pmcid: 4825810
doi: 10.1126/science.aab0983
Clarkson, B. D. S., Patel, M. S., LaFrance-Corey, R. G. & Howe, C. L. Retrograde interferon-γ signaling induces major histocompatibility class I expression in human-induced pluripotent stem cell-derived neurons. Ann. Clin. Transl Neurol. 5, 172–185 (2018).
pubmed: 29468178
doi: 10.1002/acn3.516
Kim, J.Y., Grunke, S.D., Levites, Y., Golde, T.E. & Jankowsky, J.L. Intracerebroventricular viral injection of the neonatal mouse brain for persistent and widespread neuronal transduction. J. Vis. Exp. https://doi.org/10.3791/51863 (2014).
Peng, J. et al. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat. Commun. 7, 12029 (2016).
pubmed: 27349690
pmcid: 4931235
doi: 10.1038/ncomms12029
Gittins, R. & Harrison, P. J. Neuronal density, size and shape in the human anterior cingulate cortex: a comparison of Nissl and NeuN staining. Brain Res. Bull. 63, 155–160 (2004).
pubmed: 15130705
doi: 10.1016/j.brainresbull.2004.02.005
Pang, Y. P. FF12MC: a revised AMBER forcefield and new protein simulation protocol. Proteins 84, 1490–1516 (2016).
pubmed: 27348292
pmcid: 5129589
doi: 10.1002/prot.25094
Jorgensen, W. L., Chandreskhar, J., Madura, J. D., Impey, R. W. & Klein, M. L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys. 79, 926–935 (1983).
doi: 10.1063/1.445869
Pang, Y.-P. Use of 1–4 interaction scaling factors to control the conformational equilibrium between α-helix and β-strand. Biochem. Biophys. Res. Commun. 457, 183–186 (2015).
pubmed: 25543060
doi: 10.1016/j.bbrc.2014.12.084
Larini, L., Mannella, R. & Leporini, D. Langevin stabilization of molecular-dynamics simulations of polymers by means of quasisymplectic algorithms. J. Chem. Phys. 126, 104101 (2007).
pubmed: 17362055
doi: 10.1063/1.2464095
Darden, T. A., York, D. M. & Pedersen, L. G. Particle mesh Ewald: an N log(N) method for Ewald sums in large systems. J. Chem. Phys. 98, 10089–10092 (1993).
doi: 10.1063/1.464397
Pang, Y. P. Low-mass molecular dynamics simulation for configurational sampling enhancement: more evidence and theoretical explanation. Biochem. Biophys. Rep. 4, 126–133 (2015).
pubmed: 29124195
pmcid: 5668912
Joung, I. S. & Cheatham, T. E. Determination of alkali and halide monovalent ion parameters for use in explicitly solvated biomolecular simulations. J. Phys. Chem. B 112, 9020–9041 (2008).
pubmed: 18593145
pmcid: 2652252
doi: 10.1021/jp8001614
Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020).
pubmed: 32866962
pmcid: 7746606
doi: 10.1038/s41586-020-2709-7
Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47, D442–D450 (2019).
pubmed: 30395289