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TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading

Molecular Psychiatry volume 26, pages 5925–5939 (2021)Cite this article

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Abstract

Neurofibrillary tangles (NFTs) composed of hyperphosphorylated and misfolded tau protein are a pathological hallmark of Alzheimer’s disease and other tauopathy conditions. Tau is predominantly an intraneuronal protein but is also secreted in physiological and pathological conditions. The extracellular tau has been implicated in the seeding and propagation of tau pathology and is the prime target of the current tau immunotherapy. However, truncated tau species lacking the microtubule-binding repeat (MTBR) domains essential for seeding have been shown to undergo active secretion and the mechanisms and functional consequences of the various extracellular tau are poorly understood. We report here that the transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, plays an essential role in the lysosomal exocytosis of selected tau species. TFEB loss of function significantly reduced the levels of interstitial fluid (ISF) tau in PS19 mice expressing P301S mutant tau and in conditioned media of mutant tau expressing primary neurons, while the secretion of endogenous wild-type tau was not affected. Mechanistically we found that TFEB regulates the secretion of truncated mutant tau lacking MTBR and this process is dependent on the lysosomal calcium channel TRPML1. Consistent with the seeding-incompetent nature of the truncated tau and supporting the concept that TFEB-mediated lysosomal exocytosis promotes cellular clearance, we show that reduced ISF tau in the absence of TFEB is associated with enhanced intraneuronal pathology and accelerated spreading. Our results support the idea that TFEB-mediated tau exocytosis serves as a clearance mechanism to reduce intracellular tau under pathological conditions and that effective tau immunotherapy should devoid targeting these extracellular tau species.

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Fig. 1: TFEB loss of function reduces ISF tau in PS19, but not wild-type mice.
Fig. 2: TFEB mediates the release of truncated mutant tau in primary neurons.
Fig. 3: TFEB mediates mutant tau release in HeLa cells and iPSC-derived neurons.
Fig. 4: TFEB-mediated mutant tau release requires TRPML1.
Fig. 5: TFEB cKO augments tau pathology in vitro and in vivo.
Fig. 6: TFEB cKO increases pathological tau spreading in vivo.

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References

  1. Lee VM, Goedert M, Trojanowski JQ. Neurodegenerative tauopathies. Annu Rev Neurosci. 2001;24:1121–59.

    CAS  PubMed  Google Scholar 

  2. Mandelkow EM, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2:a006247.

    PubMed  PubMed Central  Google Scholar 

  3. Gendron TF, Petrucelli L. The role of tau in neurodegeneration. Mol Neurodegener. 2009;4:13.

    PubMed  PubMed Central  Google Scholar 

  4. Wisniewski T, Goni F. Immunotherapeutic approaches for Alzheimer’s disease. Neuron. 2015;85:1162–76.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Panza F, Lozupone M, Logroscino G, Imbimbo BP. A critical appraisal of amyloid-beta-targeting therapies for Alzheimer disease. Nat Rev Neurol. 2019;15:73–88.

    PubMed  Google Scholar 

  6. Karran E, De Strooper B. The amyloid cascade hypothesis: are we poised for success or failure? J Neurochem. 2016;139 (Suppl 2):237–52.

    CAS  PubMed  Google Scholar 

  7. Giannakopoulos P, Herrmann FR, Bussiere T, Bouras C, Kovari E, Perl DP, et al. Tangle and neuron numbers, but not amyloid load, predict cognitive status in Alzheimer’s disease. Neurology. 2003;60:1495–500.

    CAS  PubMed  Google Scholar 

  8. Hanseeuw BJ, Betensky RA, Jacobs HIL, Schultz AP, Sepulcre J, Becker JA, et al. Association of amyloid and Tau with cognition in preclinical alzheimer disease: a longitudinal study. JAMA Neurol. 2019;76:915–24.

    PubMed  PubMed Central  Google Scholar 

  9. Khanna MR, Kovalevich J, Lee VM, Trojanowski JQ, Brunden KR. Therapeutic strategies for the treatment of tauopathies: hopes and challenges. Alzheimers Dement. 2016;12:1051–65.

    PubMed  PubMed Central  Google Scholar 

  10. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82:239–59.

    CAS  PubMed  Google Scholar 

  11. Frost B, Jacks RL, Diamond MI. Propagation of tau misfolding from the outside to the inside of a cell. J Biol Chem. 2009;284:12845–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Guo JL, Lee VM. Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem. 2011;286:15317–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Clavaguera F, Bolmont T, Crowther RA, Abramowski D, Frank S, Probst A, et al. Transmission and spreading of tauopathy in transgenic mouse brain. Nat Cell Biol. 2009;11:909–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. de Calignon A, Polydoro M, Suarez-Calvet M, William C, Adamowicz DH, Kopeikina KJ, et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron. 2012;73:685–97.

    PubMed  PubMed Central  Google Scholar 

  15. Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer’s-like tauopathy. J Neurosci. 2013;33:1024–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, et al. Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron. 2014;82:1271–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yamada K, Cirrito JR, Stewart FR, Jiang H, Finn MB, Holmes BB, et al. In vivo microdialysis reveals age-dependent decrease of brain interstitial fluid tau levels in P301S human tau transgenic mice. J Neurosci. 2011;31:13110–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Wu JW, Hussaini SA, Bastille IM, Rodriguez GA, Mrejeru A, Rilett K, et al. Neuronal activity enhances tau propagation and tau pathology in vivo. Nat Neurosci. 2016;19:1085–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Chai X, Wu S, Murray TK, Kinley R, Cella CV, Sims H, et al. Passive immunization with anti-Tau antibodies in two transgenic models: reduction of Tau pathology and delay of disease progression. J Biol Chem. 2011;286:34457–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Yanamandra K, Jiang H, Mahan TE, Maloney SE, Wozniak DF, Diamond MI, et al. Anti-tau antibody reduces insoluble tau and decreases brain atrophy. Ann Clin Transl Neurol. 2015;2:278–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Yanamandra K, Kfoury N, Jiang H, Mahan TE, Ma S, Maloney SE, et al. Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron. 2013;80:402–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Toledo JB, Xie SX, Trojanowski JQ, Shaw LM. Longitudinal change in CSF Tau and Abeta biomarkers for up to 48 months in ADNI. Acta Neuropathol. 2013;126:659–70.

    CAS  PubMed  Google Scholar 

  23. Saman S, Kim W, Raya M, Visnick Y, Miro S, Saman S, et al. Exosome-associated tau is secreted in tauopathy models and is selectively phosphorylated in cerebrospinal fluid in early Alzheimer disease. J Biol Chem. 2012;287:3842–9.

    CAS  PubMed  Google Scholar 

  24. Karch CM, Jeng AT, Goate AM. Extracellular Tau levels are influenced by variability in Tau that is associated with tauopathies. J Biol Chem. 2012;287:42751–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Chai X, Dage JL, Citron M. Constitutive secretion of tau protein by an unconventional mechanism. Neurobiol Dis. 2012;48:356–66.

    CAS  PubMed  Google Scholar 

  26. Morris M, Knudsen GM, Maeda S, Trinidad JC, Ioanoviciu A, Burlingame AL, et al. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat Neurosci. 2015;18:1183–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Song L, Lu SX, Ouyang X, Melchor J, Lee J, Terracina G, et al. Analysis of tau post-translational modifications in rTg4510 mice, a model of tau pathology. Mol Neurodegener. 2015;10:14.

    PubMed  PubMed Central  Google Scholar 

  28. Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM, et al. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009;18:4153–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Michel CH, Kumar S, Pinotsi D, Tunnacliffe A, St George-Hyslop P, Mandelkow E, et al. Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology. J Biol Chem. 2014;289:956–67.

    CAS  PubMed  Google Scholar 

  30. Mirbaha H, Chen D, Morazova OA, Ruff KM, Sharma AM, Liu X, et al. Inert and seed-competent tau monomers suggest structural origins of aggregation. Elife. 2018;7:e36584.

    PubMed  PubMed Central  Google Scholar 

  31. Meredith JE Jr, Sankaranarayanan S, Guss V, Lanzetti AJ, Berisha F, Neely RJ, et al. Characterization of novel CSF Tau and ptau biomarkers for Alzheimer’s disease. PLoS ONE. 2013;8:e76523.

    CAS  PubMed  Google Scholar 

  32. Kanmert D, Cantlon A, Muratore CR, Jin M, O’Malley TT, Lee G, et al. C-terminally truncated forms of Tau, but not full-length Tau or Its C-terminal fragments, are released from neurons independently of cell death. J Neurosci. 2015;35:10851–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Sato C, Barthelemy NR, Mawuenyega KG, Patterson BW, Gordon BA, Jockel-Balsarotti J, et al. Tau kinetics in neurons and the human central nervous system. Neuron. 2018;97:1284–98. e1287

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. Science. 2009;325:473–7.

    CAS  PubMed  Google Scholar 

  35. Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, et al. Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Mol Med. 2014;6:1142–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Settembre C, De Cegli R, Mansueto G, Saha PK, Vetrini F, Visvikis O, et al. TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop. Nat Cell Biol. 2013;15:647–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu Y, Zhang S, Zheng H. The cargo receptor SQSTM1 ameliorates neurofibrillary tangle pathology and spreading through selective targeting of pathological MAPT (microtubule associated protein tau). Autophagy. 2019;15:583–98.

    CAS  PubMed  Google Scholar 

  38. Xu Y, Martini-Stoica H, Zheng H. A seeding based cellular assay of tauopathy. Mol Neurodegener. 2016;11:32.

    PubMed  PubMed Central  Google Scholar 

  39. Nezich CL, Wang C, Fogel AI, Youle RJ. MiT/TFE transcription factors are activated during mitophagy downstream of Parkin and Atg5. J Cell Biol. 2015;210:435–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, et al. A comprehensive resource for induced pluripotent stem cells from patients with primary tauopathies. Stem Cell Rep. 2019;13:939–55.

    CAS  Google Scholar 

  41. Jiang S, Wen N, Li Z, Dube U, Del Aguila J, Budde J, et al. Integrative system biology analyses of CRISPR-edited iPSC-derived neurons and human brains reveal deficiencies of presynaptic signaling in FTLD and PSP. Transl Psychiatry. 2018;8:265.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Abu-Remaileh M, Wyant GA, Kim C, Laqtom NN, Abbasi M, Chan SH, et al. Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes. Science. 2017;358:807–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Yamada K, Holth JK, Liao F, Stewart FR, Mahan TE, Jiang H, et al. Neuronal activity regulates extracellular tau in vivo. J Exp Med. 2014;211:387–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Croft CL, Wade MA, Kurbatskaya K, Mastrandreas P, Hughes MM, Phillips EC, et al. Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death Dis. 2017;8:e2671.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Medina DL, Fraldi A, Bouche V, Annunziata F, Mansueto G, Spampanato C, et al. Transcriptional activation of lysosomal exocytosis promotes cellular clearance. Dev Cell. 2011;21:421–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. LaPlante JM, Sun M, Falardeau J, Dai D, Brown EM, Slaugenhaupt SA, et al. Lysosomal exocytosis is impaired in mucolipidosis type IV. Mol Genet Metab. 2006;89:339–48.

    CAS  PubMed  Google Scholar 

  47. Martini-Stoica H, Cole AL, Swartzlander DB, Chen F, Wan YW, Bajaj L, et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J Exp Med. 2018;215:2355–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Martini-Stoica H, Xu Y, Ballabio A, Zheng H. The autophagy-lysosomal pathway in neurodegeneration: a TFEB perspective. Trends Neurosci. 2016;39:221–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tsunemi T, Perez-Rosello T, Ishiguro Y, Yoroisaka A, Jeon S, Hamada K, et al. Increased lysosomal exocytosis induced by lysosomal Ca(2+) channel agonists protects human dopaminergic neurons from alpha-synuclein toxicity. J Neurosci. 2019;39:5760–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Luo W, Liu W, Hu X, Hanna M, Caravaca A, Paul SM. Microglial internalization and degradation of pathological tau is enhanced by an anti-tau monoclonal antibody. Sci Rep. 2015;5:11161.

    PubMed  PubMed Central  Google Scholar 

  51. Audrain M, Haure-Mirande JV, Wang M, Kim SH, Fanutza T, Chakrabarty P, et al. Integrative approach to sporadic Alzheimer’s disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau. Mol Psychiatry. 2019;24:1383–97.

    CAS  PubMed  Google Scholar 

  52. Asai H, Ikezu S, Tsunoda S, Medalla M, Luebke J, Haydar T, et al. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat Neurosci. 2015;18:1584–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Hopp SC, Lin Y, Oakley D, Roe AD, DeVos SL, Hanlon D, et al. The role of microglia in processing and spreading of bioactive tau seeds in Alzheimer’s disease. J Neuroinflammation. 2018;15:269.

    PubMed  PubMed Central  Google Scholar 

  54. Wang Y, Balaji V, Kaniyappan S, Kruger L, Irsen S, Tepper K, et al. The release and trans-synaptic transmission of Tau via exosomes. Mol Neurodegener. 2017;12:5.

    PubMed  PubMed Central  Google Scholar 

  55. Holth JK, Fritschi SK, Wang C, Pedersen NP, Cirrito JR, Mahan TE, et al. The sleep-wake cycle regulates brain interstitial fluid tau in mice and CSF tau in humans. Science. 2019;363:880–4.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We are grateful to R. Youle (NIH) for the gift of TFEB KO and TFEB, MITF and TFE3 TKO HeLa cells, M. Sardiello for the TFEB overexpressing TFEB HeLa line, C. Cook and L. Petrucelli for the tau-P301L expression vector and virus, and P. Davies (Feinstein Institute for Medical Research) for PHF1 and MC1 antibodies. We thank F. Stewart, B. Contreras, and N. Aithmitti for expert technical assistance and members of the Zheng laboratory for insightful discussions. This project was supported by the Gene Vector Core of Baylor College of Medicine and by grants from the NIH (R01 NS093652, R01 AG020670, and RF1 AG054111 and R01 AG057509 to HZ; R01 AG062734, R56 NS110980 to CMK), the Tau Consortium, and the Farrell Family Alzheimer’s Disease Research Fund (to CMK).

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Authors and Affiliations

  1. Huffington Center on Aging, Baylor College of Medicine, Houston, TX, USA

    Yin Xu, Shuqi Du & Hui Zheng

  2. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Shuqi Du & Hui Zheng

  3. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

    Jacob A. Marsh & Celeste M. Karch

  4. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    Kanta Horie, Chihiro Sato & David M. Holtzman

  5. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    Andrea Ballabio & Hui Zheng

  6. Dan and Jan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

    Andrea Ballabio

  7. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy

    Andrea Ballabio

  8. Department of Medical and Translational Sciences, Federico II University, Naples, Italy

    Andrea Ballabio

  9. Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA

    Celeste M. Karch & David M. Holtzman

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Contributions

YX and HZ designed the study; YX, with assistance from SD, performed all experiments and data analysis except iPSCs and in vivo microdialysis experiments, which were performed and analyzed in the CMK laboratory (JAM, KH, CS, CMK) and the DMH laboratory, respectively; AB provided Tcfeb floxed mice and advised some of the in vitro studies; YX and HZ wrote the paper with edits and critiques from DMH. All authors provided input, and read and approved the manuscript.

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Correspondence to Yin Xu or Hui Zheng.

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Xu, Y., Du, S., Marsh, J.A. et al. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Mol Psychiatry 26, 5925–5939 (2021). https://doi.org/10.1038/s41380-020-0738-0

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