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Nature neuroscience
01, 2022;25 (1): 26-38.

TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration.

Manling Xie, Yong U Liu, Shunyi Zhao, Lingxin Zhang, Dale B Bosco, Yuan-Ping Pang, Jun Zhong, Udit Sheth, Yuka A Martens, Na Zhao, Chia-Chen Liu, Yongxian Zhuang, Liewei Wang, Dennis W Dickson, Mark P Mattson, Guojun Bu, Long-Jun Wu
Author Information
  1. Manling Xie: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  2. Yong U Liu: Department of Neurology, Mayo Clinic, Rochester, MN, USA. liuy6@foxmail.com. ORCID
  3. Shunyi Zhao: Department of Neurology, Mayo Clinic, Rochester, MN, USA. ORCID
  4. Lingxin Zhang: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
  5. Dale B Bosco: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
  6. Yuan-Ping Pang: Computer-Aided Molecular Design Laboratory, Mayo Clinic, Rochester, MN, USA. ORCID
  7. Jun Zhong: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. ORCID
  8. Udit Sheth: Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA.
  9. Yuka A Martens: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. ORCID
  10. Na Zhao: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. ORCID
  11. Chia-Chen Liu: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. ORCID
  12. Yongxian Zhuang: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
  13. Liewei Wang: Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA. ORCID
  14. Dennis W Dickson: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. ORCID
  15. Mark P Mattson: Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  16. Guojun Bu: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. ORCID
  17. Long-Jun Wu: Department of Neurology, Mayo Clinic, Rochester, MN, USA. wu.longjun@mayo.edu. ORCID
PMID: 34916658 DOI: 10.1038/s41593-021-00975-6

Abstract

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.

References

  1. Hickman, S., Izzy, S., Sen, P., Morsett, L. & El Khoury, J. Microglia in neurodegeneration. Nat. Neurosci. 21, 1359–1369 (2018). [PMID: 30258234]
  2. Ulland, T. K. & Colonna, M. TREM2—a key player in microglial biology and Alzheimer disease. Nat. Rev. Neurol. 14, 667–675 (2018). [PMID: 30266932]
  3. Guerreiro, R. et al. TREM2 variants in Alzheimer’s disease. N. Engl. J. Med. 368, 117–127 (2013). [PMID: 23150934]
  4. Jonsson, T. et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N. Engl. J. Med. 368, 107–116 (2013). [PMID: 23150908]
  5. Wang, Y. et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160, 1061–1071 (2015). [PMID: 25728668]
  6. Zhao, Y. et al. TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron 97, 1023–1031 (2018). [PMID: 29518356]
  7. 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). [PMID: 7745706]
  8. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006). [PMID: 17023659]
  9. Cairns, N. J. et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am. J. Pathol. 171, 227–240 (2007). [PMID: 17591968]
  10. Cady, J. et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 71, 449–453 (2014). [PMID: 24535663]
  11. 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). [PMID: 23800361]
  12. Krasemann, S. et al. The TREM2–APOE pathway drives the transcriptional phenotype of dysfunctional microglia in neurodegenerative diseases. Immunity 47, 566–581 (2017). [PMID: 28930663]
  13. Maniatis, S. et al. Spatiotemporal dynamics of molecular pathology in amyotrophic lateral sclerosis. Science 364, 89–93 (2019). [PMID: 30948552]
  14. 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). [PMID: 26197969]
  15. Perry, V. H., Nicoll, J. A. & Holmes, C. Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193–201 (2010). [PMID: 20234358]
  16. 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). [PMID: 29426702]
  17. Keren-Shaul, H. et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169, 1276–1290 (2017). [PMID: 28602351]
  18. Eyo, U. B. et al. P2Y12R-dependent translocation mechanisms gate the changing microglial landscape. Cell Rep. 23, 959–966 (2018). [PMID: 29694903]
  19. 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). [PMID: 29463850]
  20. 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). [PMID: 19001167]
  21. 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]
  22. 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). [PMID: 29786080]
  23. 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). [PMID: 22127299]
  24. Li, Q. et al. Developmental heterogeneity of microglia and brain myeloid cells revealed by deep single-cell RNA sequencing. Neuron 101, 207–223 (2019). [PMID: 30606613]
  25. Liu, Y. U. et al. Neuronal network activity controls microglial process surveillance in awake mice via norepinephrine signaling. Nat. Neurosci. 22, 1771–1781 (2019). [PMID: 31636449]
  26. Parhizkar, S. et al. Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nat. Neurosci. 22, 191–204 (2019). [PMID: 30617257]
  27. Leyns, C. E. G. et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 22, 1217–1222 (2019). [PMID: 31235932]
  28. 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). [PMID: 29518357]
  29. Konishi, H. & Kiyama, H. Microglial TREM2/DAP12 signaling: a double-edged sword in neural diseases. Front. Cell. Neurosci. 12, 206 (2018). [PMID: 30127720]
  30. Mazaheri, F. et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep. 18, 1186–1198 (2017). [PMID: 28483841]
  31. Zheng, H. et al. TREM2 promotes microglial survival by activating Wnt/β-catenin pathway. J. Neurosci. 37, 1772–1784 (2017). [PMID: 28077724]
  32. Guan, Z. et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016). [PMID: 26642091]
  33. 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). [PMID: 27373153]
  34. 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). [PMID: 19503107]
  35. Brown, G. C. & Neher, J. J. Microglial phagocytosis of live neurons. Nat. Rev. Neurosci. 15, 209–216 (2014). [PMID: 24646669]
  36. 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). [PMID: 24395130]
  37. Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352, 712–716 (2016). [PMID: 27033548]
  38. Koizumi, S. et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature 446, 1091–1095 (2007). [PMID: 17410128]
  39. Tufail, Y. et al. Phosphatidylserine exposure controls viral innate immune responses by microglia. Neuron 93, 574–586 e578 (2017). [PMID: 28111081]
  40. Das, R. & Chinnathambi, S. Microglial priming of antigen presentation and adaptive stimulation in Alzheimer’s disease. Cell. Mol. Life Sci. 76, 3681–3694 (2019). [PMID: 31093687]
  41. 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). [PMID: 23739956]
  42. 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). [PMID: 18386786]
  43. 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). [PMID: 29507931]
  44. Sato-Hashimoto, M. et al. Microglial SIRPα regulates the emergence of CD11c microglia and demyelination damage in white matter. eLife 8, e4202 (2019). [DOI: 10.7554/eLife.42025]
  45. 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). [PMID: 26374899]
  46. Feiler, M. S. et al. TDP-43 is intercellularly transmitted across axon terminals. J. Cell Biol. 211, 897–911 (2015). [PMID: 26598621]
  47. Zhong, L. et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model. Nat. Commun. 10, 1365 (2019). [PMID: 30911003]
  48. Kober, D. L. et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife 5, e20391 (2016). [PMID: 27995897]
  49. 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). [PMID: 27477018]
  50. 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). [PMID: 26250685]
  51. 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). [PMID: 29468178]
  52. 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).
  53. Peng, J. et al. Microglia and monocytes synergistically promote the transition from acute to chronic pain after nerve injury. Nat. Commun. 7, 12029 (2016). [PMID: 27349690]
  54. 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). [PMID: 15130705]
  55. Pang, Y. P. FF12MC: a revised AMBER forcefield and new protein simulation protocol. Proteins 84, 1490–1516 (2016). [PMID: 27348292]
  56. 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]
  57. 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). [PMID: 25543060]
  58. 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). [PMID: 17362055]
  59. 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]
  60. Pang, Y. P. Low-mass molecular dynamics simulation for configurational sampling enhancement: more evidence and theoretical explanation. Biochem. Biophys. Rep. 4, 126–133 (2015). [PMID: 29124195]
  61. 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). [PMID: 18593145]
  62. Zhang, J. et al. Neurotoxic microglia promote TDP-43 proteinopathy in progranulin deficiency. Nature 588, 459–465 (2020). [PMID: 32866962]
  63. 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). [PMID: 30395289]

Grants

  1. R01 NS110949/NINDS NIH HHS
  2. U19 AG069701/NIA NIH HHS
  3. R01 AG066395/NIA NIH HHS
  4. R21 AG064159/NIA NIH HHS
  5. R01 NS088627/NINDS NIH HHS

MeSH Term

Animals
DNA-Binding Proteins
Membrane Glycoproteins
Mice
Mice, Transgenic
Microglia
Neurodegenerative Diseases
Neuroprotection
Receptors, Immunologic

Chemicals

DNA-Binding Proteins
Membrane Glycoproteins
Receptors, Immunologic
TDP-43 protein, mouse
Trem2 protein, mouse
Journal Article Research Support, N.I.H., Extramural
Article has an altmetric score of 85

Word Cloud

Created with Highcharts 10.0.0TREM2TDP-43neurodegenerationmicroglialmicrogliaphagocyticanalysishumanhTDP-43interactionmediatesneuroprotectionTDP-43-relatedTriggeringreceptorexpressedmyeloidcell2linkedriskneurodegenerativediseaseHoweverfunctionstillfullyunderstoodinvestigatedroleTARDNA-bindingprotein43-relatedusingvirus-mediatedtransgenicmousemodelsfounddeficiencyimpairedclearancepathologicalenhancedneuronaldamagemotorimpairmentsMasscytometryrevealedinducedTREM2-dependentsubpopulationhighCD11cexpressionabilityUsingmassspectrometryMSsurfaceplasmonresonanceSPRdemonstratedvitrovivowelltissuesindividualsamyotrophiclateralsclerosisALScomputationallyidentifiedregionswithininteractdatahighlightpossibleligandinteracts

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