CoChat
Sign Up
Cited by 424Alzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment Research

MAPT mutations, tauopathy, and mechanisms of neurodegeneration

Open access
Strang, Kevin H., Golde, Todd E., Giasson, Benoit I.·2019·Laboratory Investigation
DOI 10.1038/s41374-019-0197-xPMC PMC7289372
Open this paper in CoChat — free accountOpen PDF

Abstract

In multiple neurodegenerative diseases, including Alzheimer's disease (AD), a prominent pathological feature is the aberrant aggregation and inclusion formation of the microtubule-associated protein tau. Because of the pathological association, these disorders are often referred to as tauopathies. Mutations in the MAPT gene that encodes tau can cause frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), providing the clearest evidence that tauopathy plays a causal role in neurodegeneration. However, large gaps in our knowledge remain regarding how various FTDP-17-linked tau mutations promote tau aggregation and neurodegeneration, and, more generally, how the tauopathy is linked to neurodegeneration. Herein, we review what is known about how FTDP-17-linked pathogenic MAPT mutations cause disease, with a major focus on the prion-like properties of wild-type and mutant tau proteins. The hypothesized mechanisms by which mutations in the MAPT gene promote tauopathy are quite varied and may not provide definitive insights into how tauopathy arises in the absence of mutation. Further, differences in the ability of tau and mutant tau proteins to support prion-like propagation in various model systems raise questions about the generalizability of this mechanism in various tauopathies. Notably, understanding the mechanisms of tauopathy induction and spread and tau-induced neurodegeneration has important implications for tau-targeting therapeutics.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41374-019-0197-x

Cites

25 of 25 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Effects of tauopathy on DTI metrics in grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies.

    “Effects of tauopathy on DTI metrics in the grey and white matter are complex and may involve axonal damage, myelin injury, neuronal degeneration, and gliosis, which all have been found in tauopathies [17,18,23,25,28,29,33,38,57].”

    From Diffusion tensor imaging reveals whole-brain microstructural changes in the P301L mouse model of tauopathy. (2020) · cites this paper as [23]

    The Introduction describes neurodegeneration and tau inclusions in neurons and sometimes glia; “Impacts of Tau Mutations on Aggregation and Seeding” discusses impaired axonal transport as a possible mechanism. Our copy does not link these findings to grey- or white-matter DTI metrics, or report myelin injury or gliosis. Glial tau inclusions do not themselves establish gliosis. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 161

  1. [1]Arendt T, Stieler JT, Holzer M. Tau and tauopathies. Brain Res Bull 2016; 126: 238– 92. 27615390
  2. [2]Couchie D, Mavilia C, Georgieff IS, Liem RK, Shelanski ML, Nunez J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc Natl Acad Sci 1992; 89: 4378– 81. 1374898 PMC49085
  3. [3]Caillet-Boudin M-L, Buée L, Sergeant N, Lefebvre B. Regulation of human MAPT gene expression. Mol Neurodegener 2015; 10: 1– 14. 26170022 PMC4499907
  4. [4]Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell 1992; 3: 1141– 54. 1421571 PMC275678
  5. [5]Guo T, Noble W, Hanger DP. Roles of tau protein in health and disease. Acta Neuropathol 2017; 133: 665– 704. 28386764 PMC5390006
  6. [6]Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci U S A 1975; 72: 1858– 62. 1057175 PMC432646
  7. [7]Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci U S A 1986; 83: 4913– 7. 3088567 PMC323854
  8. [9]Poorkaj P, Bird TD, Wijsman E, Nemens E, Garruto RM, Anderson L, Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998; 43: 815– 25. 9629852
  9. [10]Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci 1998; 95: 7737– 41. 9636220 PMC22742
  10. [11]Ghetti B, Oblak AL, Boeve BF, Johnson KA, Dickerson BC, Goedert M. Invited review: Frontotemporal dementia caused by microtubule-associated protein tau gene (MAPT) mutations: A chameleon for neuropathology and neuroimaging. Neuropathol Appl Neurobiol 2015; 41: 24– 46. 25556536 PMC4329416
  11. [12]Reed LA, Wszolek ZK, Hutton M. Phenotypic correlations in FTDP-17. Neurobiol Aging 2001; 22: 89– 107. 11164280
  12. [13]Poorkaj P, Muma NA, Zhukareva V, Cochran EJ, Shannon KM, Hurtig H, An R5L τ mutation in a subject with a progressive supranuclear palsy phenotype. Ann Neurol 2002; 52: 511– 6. 12325083
  13. [14]Kouri N, Carlomagno Y, Baker M, Liesinger AM, Caselli RJ, Wszolek ZK, Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration. Acta Neuropathol 2014; 127: 271– 82. 24121548 PMC3943649
  14. [15]Rizzini C, Goedert M, Hodges JR, Smith MJ, Jakes R, Hills R, Tau gene mutation K257T causes a tauopathy similar to Pick’s disease. J Neuropathol Exp Neurol 2000; 59: 990– 1001. 11089577
  15. [16]Forrest SL, Kril JJ, Stevens CH, Kwok JB, Hallupp M, Kim WS, Retiring the term FTDP-17 as MAPT mutations are genetic forms of sporadic frontotemporal tauopathies. Brain 2017; 141: 521– 34. PMC5888940 29253099
  16. [17]Coppola G, Chinnathambi S, Lee JJY, Dombroski BA, Baker MC, Soto-ortolaza AI, Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer’s diseases. Hum Mol Genet 2012; 21: 3500– 12. 22556362 PMC3392107
  17. [18]Liu F, Gong C-X. Tau exon 10 alternative splicing and tauopathies. Mol Neurodegener 2008; 3: 8. 18616804 PMC2483273
  18. [19]Kosik KS, Orecchio LD, Bakalis S, Neve RL. Developmentally regulated expression of specific tau sequences. Neuron 1989; 2: 1389– 97. 2560640
  19. [20]Goedert M, Spillantini MG, Jakes R, Rutherford D, Crowther RA. Multiple isoforms of human microtubule-associated protein tau: sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989; 3: 519– 26. 2484340
  20. [21]Majounie E, Cross W, Newsway V, Dillman A, Vandrovcova J, Morris CM, Variation in tau isoform expression in different brain regions and disease states. Neurobiol Aging 2013; 34: 1922.e7– 1922.e12. PMC3642280 23428180
  21. [23]Goode BL, Chau M, Denis PE, Feinstein SC. Structural and functional differences between 3-repeat and 4-repeat tau isoforms: Implications for normal tau function and the onset of neurodegenerative disease. J Biol Chem 2000; 275: 38182– 9. 10984497
  22. [24]Lu M, Kosik KS. Competition for microtubule-binding with dual expression of tau missense and splice isoforms. Mol Biol Cell 2001; 12: 171– 84. 11160831 PMC30576
  23. [25]Niblock M, Gallo J. Tau alternative splicing in familial and sporadic tauopathies. Biochem Soc Trans 2012; 40: 677– 80. 22817715
  24. [26]Derisbourg M, Leghay C, Chiappetta G, Fernandez-Gomez FJ, Laurent C, Demeyer D, Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci Rep 2015; 5: 9659. 25974414 PMC4431475
  25. [27]Liu C, Song X, Nisbet R, Götz J. Co-immunoprecipitation with Tau isoform-specific antibodies reveals distinct protein interactions and highlights a putative role for 2N Tau in disease. J Biol Chem 2016; 291: 8173– 88. 26861879 PMC4825019
  26. [28]Trabzuni D, Wray S, Vandrovcova J, Ramasamy A, Walker R, Smith C, MAPT expression and splicing is differentially regulated by brain region: Relation to genotype and implication for tauopathies. Hum Mol Genet 2012; 21: 4094– 103. 22723018 PMC3428157
  27. [29]Qian W, Liu F. Regulation of alternative splicing of tau exon 10. Neurosci. Bull. 2014; 30; 367– 77. 24627328 PMC5562657
  28. [30]D’Souza I, Schellenberg GD. Determinants of 4-repeat tau expression. Coordination between enhancing and inhibitory splicing sequences for exon 10 inclusion. J Biol Chem 2000; 275: 17700– 9. 10748133
  29. [31]Pittman AM, Myers AJ, Duckworth J, Bryden L, Hanson M, Abou-Sleiman P, The structure of the tau haplotype in controls and in progressive supranuclear palsy. Hum Mol Genet 2004; 13: 1267– 74. 15115761
  30. [32]Pittman AM, Fung HC, de Silva R. Untangling the tau gene association with neurodegenerative disorders. Hum Mol Genet 2006; 15: 188– 95. 16987883
  31. [34]Myers AJ, Pittman AM, Zhao AS, Rohrer K, Kaleem M, Marlowe L, The MAPT H1c risk haplotype is associated with increased expression of tau and especially of 4 repeat containing transcripts. Neurobiol Dis 2007; 25: 561– 70. 17174556
  32. [35]Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, Structural polymorphism of 441-residue Tau at single residue resolution. PLoS Biol 2009; 7: 0399– 414. PMC2642882 19226187
  33. [37]Jeganathan S, Von Bergen M, Brutlach H, Steinhoff HJ, Mandelkow E. Global hairpin folding of tau in solution. Biochemistry 2006; 45: 2283– 93. 16475817
  34. [38]Wischik CM, Novak M, Thøgersen HC, Edwards PC, Runswick MJ, Jakes R, Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci U S A 1988; 85: 4506– 10. 3132715 PMC280459
  35. [39]Ganguly P, Do TD, Larini L, Lapointe NE, Sercel AJ, Shade MF, Tau assembly: The dominant role of PHF6 (VQIVYK) in microtubule binding region repeat R3. J Phys Chem B 2015; 119: 4582– 93. 25775228 PMC4428543
  36. [40]Smit FX, Luiken JA, Bolhuis PG. Primary Fibril Nucleation of Aggregation Prone Tau Fragments PHF6 and PHF6. J Phys Chem B 2017; 121: 3250– 61. 27776213
  37. [41]von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow EM, Mandelkow E. Assembly of tau protein into Alzheimer paired helical filaments depends on a local sequence motif ((306)VQIVYK(311)) forming beta structure. Proc Natl Acad Sci U S A 2000; 97: 5129– 34. 10805776 PMC25793
  38. [43]Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 2018; 561: 137– 40. 30158706 PMC6204212
  39. [44]Von Bergen M, Barghorn S, Biernat J, Mandelkow EM, Mandelkow E. Tau aggregation is driven by a transition from random coil to beta sheet structure. Biochim Biophys Acta - Mol Basis Dis 2005; 1739: 158– 66. 15615635
  40. [45]Friedhoff P, von Bergen M, Mandelkow EM, Davies P, Mandelkow E. A nucleated assembly mechanism of Alzheimer paired helical filaments. Proc Natl Acad Sci U S A 1998; 95: 15712– 7. 9861035 PMC28109
  41. [47]Shammas SL, Garcia GA, Kumar S, Kjaergaard M, Horrocks MH, Shivji N, A mechanistic model of tau amyloid aggregation based on direct observation of oligomers. Nat Commun 2015; 6: 7025. 25926130 PMC4421837
  42. [48]Wegmann S, Eftekharzadeh B, Tepper K, Zoltowska KM, Bennett RE, Dujardin S, Tau protein liquid–liquid phase separation can initiate tau aggregation. EMBO J 2018; e98049. 29472250 PMC5881631
  43. [49]Goedert M, Masuda-Suzukake M, Falcon B. Like prions: The propagation of aggregated tau and α-synuclein in neurodegeneration. Brain 2017; 140: 266– 78. 27658420
  44. [50]Prusiner S Novel proteinaceous infectious particles cause scrapie. Science 1982; 216: 136– 44. 6801762
  45. [51]Braak H, Braak E. Staging of alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 1995; 16: 271– 8. 7566337
  46. [52]Ayers JI, Giasson BI, Borchelt DR. Prion-like Spreading in Tauopathies. Biol Psychiatry 2018; 83: 337– 46. 28506438 PMC5640465
  47. [53]Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci 2015; 17: 22– 35. 26631930
  48. [55]Hoover BR, Reed MN, Su J, Penrod RD, Kotilinek LA, Grant MK, Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration. Neuron 2010; 68: 1067– 81. 21172610 PMC3026458
  49. [56]Liu C, Götz J. Profiling murine tau with 0N, 1N and 2N isoform-specific antibodies in brain and peripheral organs reveals distinct subcellular localization, with the 1N isoform being enriched in the nucleus. PLoS One 2013; 8: e84849. 24386422 PMC3875548
  50. [57]Stamer K, Vogel R, Thies E, Mandelkow E, Mandelkow EM. Tau blocks traffic of organelles, neurofilaments, and APP vesicles in neurons and enhances oxidative stress. J Cell Biol 2002; 156: 1051– 63. 11901170 PMC2173473
  51. [58]Caceres A, Kosik KS. Inhibition of neurite polarity by tau antisense oligonucleotides in primary cerebellar neurons. Nature 1990; 343: 461– 3. 2105469
  52. [59]Hong X-P, Peng C-X, Wei W, Tian Q, Liu Y-H, Yao X-Q, Essential role of tau phosphorylation in adult hippocampal neurogenesis. Hippocampus 2010; 20: 1339– 49. 19816983
  53. [60]Kimura T, Whitcomb DJ, Jo J, Regan P, Piers T, Heo S, Microtubule-associated protein tau is essential for long-term depression in the hippocampus. Philos Trans R Soc Lond B Biol Sci 2014; 369: 20130144. 24298146 PMC3843876
  54. [61]Hirokawa N, Shiomura Y, Okabe S. Tau proteins: the molecular structure and mode of binding on microtubules. J Cell Biol 1988; 107: 1449– 59. 3139677 PMC2115262
  55. [62]Brandt R, Léger J, Lee G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J Cell Biol 1995; 131: 1327– 40. 8522593 PMC2120645
  56. [63]Magnani E, Fan J, Gasparini L, Golding M, Williams M, Schiavo G, Interaction of tau protein with the dynactin complex. EMBO J 2007; 26: 4546– 54. 17932487 PMC2063488
  57. [64]Kadavath H, Hofele RV, Biernat J, Kumar S, Tepper K, Urlaub H, Tau stabilizes microtubules by binding at the interface between tubulin heterodimers. Proc Natl Acad Sci U S A 2015; 112: 7501– 6. 26034266 PMC4475932
  58. [65]Thies E, Mandelkow E-M. Missorting of tau in neurons causes degeneration of synapses that can be rescued by the kinase MARK2/Par-1. J Neurosci 2007; 27: 2896– 907. 17360912 PMC6672561
  59. [66]Despres C, Byrne C, Qi H, Cantrelle F-X, Huvent I, Chambraud B, Identification of the Tau phosphorylation pattern that drives its aggregation. Proc Natl Acad Sci U S A 2017; 114: 9080– 5. 28784767 PMC5576827
  60. [67]Alonso ADC, Mederlyova A, Novak M, Grundke-Iqbal I, Iqbal K. Promotion of hyperphosphorylation by frontotemporal dementia tau mutations. J Biol Chem 2004; 279: 34873– 81. 15190058
  61. [70]Martin L, Latypova X, Terro F. Post-translational modifications of tau protein: Implications for Alzheimer’s disease. Neurochem Int 2011; 58: 458– 71. 21215781
  62. [71]Lee S, Shea TB. Caspase-mediated truncation of Tau potentiates aggregation. Int J Alzheimers Dis 2012; 2012: 731063. 22988541 PMC3440879
  63. [72]Kondo A, Shahpasand K, Mannix R, Qiu J, Moncaster J, Chen CH, Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy. Nature 2015; 523: 431– 6. 26176913 PMC4718588
  64. [73]Wang JZ, Grundke-Iqbal I, Iqbal K. Glycosylation of microtubule-associated protein tau: An abnormal posttranslational modification in Alzheimer’s disease. Nat Med 1996; 2: 871– 5. 8705855
  65. [74]Funk KE, Thomas SN, Schafer KN, Cooper GL, Clark DJ, Yang AJ, Lysine methylation is an endogenous post-translational modification of tau protein in human brain and a modulator of aggregation propensity. Biochem J 2015; 462: 77– 88. PMC4292886 24869773
  66. [75]Goedert M, Spillantini MG, Jakes R, Crowtherp RA, Vanmechelen E, Probst A, Molecular dissection of the paired helical filament. Neurobiol Aging 1995; 16: 325– 34. 7566342
  67. [76]Dickson DW, Kouri N, Murray ME, Josephs KA. Neuropathology of Frontotemporal Lobar Degeneration-Tau (FTLD-Tau). J Mol Neurosci 2012; 45: 384– 9. PMC3208128 21720721
  68. [77]D’Souza I, Schellenberg GD. Regulation of tau isoform expression and dementia. Biochim Biophys Acta - Mol Basis Dis 2005; 1739: 104– 15. 15615630
  69. [78]Stoothoff W, Jones PB, Spires-Jones TL, Joyner D, Chhabra E, Bercury K, Differential effect of three-repeat and four-repeat tau on mitochondrial axonal transport. J Neurochem 2009; 111: 417– 27. 19686388 PMC2831412
  70. [79]van Swieten JC, Bronner IF, Azmani A, Severijnen L-A, Kamphorst W, Ravid R, The ΔK280 Mutation in MAP tau Favors Exon 10 Skipping In Vivo. J Neuropathol Exp Neurol 2007; 66: 17– 25. 17204933
  71. [80]Ogaki K, Li Y, Takanashi M, Ishikawa KI, Kobayashi T, Nonaka T, Analyses of the MAPT, PGRN, and C9orf72 mutations in Japanese patients with FTLD, PSP, and CBS. Park Relat Disord 2013; 19: 15– 20. 22818528
  72. [81]Panda D, Samuel JC, Massie M, Feinstein SC, Wilson L. Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease. Proc Natl Acad Sci U S A 2003; 100: 9548– 53. 12886013 PMC170955
  73. [82]Pickering-Brown SM, Baker M, Nonaka T, Ikeda K, Sharma S, Mackenzie J, Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene. Brain 2004; 127: 1415– 26. 15047590
  74. [83]Tacik P, DeTure M, Hinkle KM, Lin WL, Sanchez-Contreras M, Carlomagno Y, A novel Tau Mutation in exon 12, P. Q336H, causes hereditary pick disease. J Neuropathol Exp Neurol 2015; 74: 1042– 52. 26426266 PMC4607649
  75. [84]D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM-Y, Bird TD, Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A 1999; 96: 5598– 603. 10318930 PMC21906
  76. [86]Dinkel PD, Holden MR, Matin N, Margittai M. RNA binds to tau fibrils and sustains template-assisted growth. Biochemistry 2015; 54: 4731– 40. 26177386 PMC4526887
  77. [87]Kampers T, Friedhoff P, Biernat J, Mandelkow EM, Mandelkow E. RNA stimulates aggregation of microtubule-associated protein tau into Alzheimer-like paired helical filaments. FEBS Lett 1996; 399: 344– 9. 8985176
  78. [89]Nonaka T, Watanabe ST, Iwatsubo T, Hasegawa M. Seeded aggregation and toxicity of α-synuclein and tau: Cellular models of neurodegenerative diseases. J Biol Chem 2010; 285: 34885– 98. 20805224 PMC2966103
  79. [91]Holmes BB, Furman JL, Mahan TE, Yamasaki TR, Mirbaha H, Eades WC, Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A 2014; 111: E4376– 4385. 25261551 PMC4205609
  80. [92]Sanders DW, Kaufman SK, DeVos SL, Sharma AM, Mirbaha H, Li A, Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 2014; 82: 1271– 88. 24857020 PMC4171396
  81. [93]Guo JL, Lee VMY. Neurofibrillary tangle-like tau pathology induced by synthetic tau fibrils in primary neurons over-expressing mutant tau. FEBS Lett 2013; 587: 717– 23. 23395797 PMC3678381
  82. [94]Falcon B, Cavallini A, Angers R, Glover S, Murray TK, Barnham L, Conformation determines the seeding potencies of native and recombinant Tau aggregates. J Biol Chem 2015; 290: 1049– 65. 25406315 PMC4294473
  83. [95]Waxman EA, Giasson BI. Induction of intracellular tau aggregation is promoted by α-synuclein seeds and provides novel insights into the hyperphosphorylation of tau. J Neurosci 2011; 31: 7604– 18. 21613474 PMC3122484
  84. [96]Guo JL, Lee VMY. Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles. J Biol Chem 2011; 286: 15317– 31. 21372138 PMC3083182
  85. [98]Boluda S, Iba M, Zhang B, Raible KM, Lee VMY, Trojanowski JQ. Differential induction and spread of tau pathology in young PS19 tau transgenic mice following intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration brains. Acta Neuropathol 2015; 129: 221– 37. 25534024 PMC4305460
  86. [99]Ahmed Z, Cooper J, Murray TK, Garn K, McNaughton E, Clarke H, A novel in vivo model of tau propagation with rapid and progressive neurofibrillary tangle pathology: The pattern of spread is determined by connectivity, not proximity. Acta Neuropathol 2014; 127: 667– 83. 24531916 PMC4252866
  87. [100]Jackson SJ, Kerridge C, Cooper J, Cavallini A, Falcon B, Cella C V, Short fibrils constitute the major species of seed-competent tau in the brains of mice transgenic for human P301S tau. J Neurosci 2016; 36: 762– 72. 26791207 PMC4719013
  88. [101]Kaufman SK, Sanders DW, Thomas TL, Ruchinskas AJ, Vaquer-Alicea J, Sharma AM, Tau prion strains dictate patterns of cell pathology, progression rate, and regional vulnerability in vivo. Neuron 2016; 92: 796– 812. 27974162 PMC5392364
  89. [102]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. 23325240 PMC3575082
  90. [104]Chakrabarty P, Hudson VJ, Sacino AN, Brooks M, D’Alton S, Lewis J, Inefficient induction and spread of seeded tau pathology in P301L mouse model tauopathy suggest inherent physiological barriers to transmission. Acta Neuropathol 2015; 130: 303– 5. 25982997 PMC4652651
  91. [106]Vasconcelos B, Stancu IC, Buist A, Bird M, Wang P, Vanoosthuyse A, Heterotypic seeding of Tau fibrillization by pre-aggregated Abeta provides potent seeds for prion-like seeding and propagation of Tau-pathology in vivo. Acta Neuropathol 2016; 131: 549– 69. 26739002 PMC4789256
  92. [107]Clavaguera F, Akatsu H, Fraser G, Crowther RA, Frank S, Hench J, Brain homogenates from human tauopathies induce tau inclusions in mouse brain. Proc Natl Acad Sci U S A 2013; 110: 9535– 40. 23690619 PMC3677441
  93. [108]Adams SJ, de Ture MA, McBride M, Dickson DW, Petrucelli L. Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. PLoS One 2010; 5: e10810. 20520830 PMC2876030
  94. [109]Strang KH, Croft CL, Sorrentino ZA, Chakrabarty P, Golde TE, Giasson BI. Distinct differences in prion-like seeding and aggregation between tau protein variants provide mechanistic insights into tauopathies. J Biol Chem 2017; 293: 2408– 21. 29259137 PMC5818185
  95. [110]Siddiqua A, Luo Y, Meyer V, Swanson MA, Yu X, Wei G, Conformational basis for asymmetric seeding barrier in filaments of three- and four-repeat tau. J Am Chem Soc 2012; 134: 10271– 8. 22656332 PMC3381011
  96. [111]Woerman AL, Aoyagi A, Patel S, Kazmi SA, Lobach I, Grinberg LT, Tau prions from Alzheimer’s disease and chronic traumatic encephalopathy patients propagate in cultured cells. Proc Natl Acad Sci 2016; 113: E8187– 96. 27911827 PMC5167200
  97. [112]Combs B, Gamblin TC. FTDP-17 tau mutations induce distinct effects on aggregation and microtubule interactions. Biochemistry 2012; 51: 8597– 607. 23043292 PMC3548947
  98. [114]Monsellier E, Chiti F. Prevention of amyloid-like aggregation as a driving force of protein evolution. EMBO Rep 2007; 8: 737– 42. 17668004 PMC1978086
  99. [115]Bardai FH, Wang L, Mutreja Y, Yenjerla M, Gamblin TC, Feany MB. A conserved cytoskeletal signaling cascade mediates neurotoxicity of FTDP-17 tau mutations in vivo. J Neurosci 2017; 38: 1550– 1517. PMC5761430 29138281
  100. [116]Rosso SM, Van Herpen E, Deelen W, Kamphorst W, Severijnen LA, Willemsen R, A novel tau mutation, S320F, causes a tauopathy with inclusions similar to those in Pick’s disease. Ann Neurol 2002; 51: 373– 6. 11891833
  101. [117]Jeganathan S, Hascher A, Chinnathambi S, Biernat J, Mandelkow EM, Mandelkow E. Proline-directed pseudo-phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of tau and generates a pathological (MC-1) conformation. J Biol Chem 2008; 283: 32066– 76. 18725412
  102. [119]Lin WL, Lewis J, Yen SH, Hutton M, Dickson DW. Ultrastructural neuronal pathology in transgenic mice expressing mutant (P301L) human tau. J Neurocytol 2003; 32: 1091– 105. 15044841
  103. [123]Spires-Jones TL, de Calignon A, Matsui T, Zehr C, Pitstick R, Wu H-Y, In vivo imaging reveals dissociation between caspase activation and acute neuronal death in tangle-bearing neurons. J Neurosci 2008; 28: 862– 7. 18216194 PMC6670992
  104. [125]Flach K, Hilbrich I, Schiffmann A, Gärtner U, Krüger M, Leonhardt M, Tau oligomers impair artificial membrane integrity and cellular viability. J Biol Chem 2012; 287: 43223– 33. 23129775 PMC3527910
  105. [126]Hayashi S, Toyoshima Y, Hasegawa M, Umeda Y, Wakabayashi K, Tokiguchi S, Late-onset frontotemporal dementia with a novel exon 1 (Arg5His) tau gene mutation. Ann Neurol 2002; 51: 525– 30. 11921059
  106. [127]Chang E, Kim S, Yin H, Nagaraja HN, Kuret J. Pathogenic missense MAPT mutations differentially modulate tau aggregation propensity at nucleation and extension steps. J Neurochem 2008; 107: 1113– 23. 18803694 PMC2596975
  107. [128]Iyer A, LaPointe NE, Zielke K, Berdynski M, Guzman E, Barczak A, A novel MAPT mutation, G55R, in a frontotemporal dementia patient leads to altered tau function. PLoS One 2013; 8: e76409. 24086739 PMC3785453
  108. [129]Silva MC, Cheng C, Mair W, Almeida S, Fong H, Biswas MHU, Human iPSC-derived neuronal model of Tau-A152T frontotemporal dementia reveals tau-mediated mechanisms of neuronal vulnerability. Stem Cell Reports 2016; 7: 325– 40. 27594585 PMC5032560
  109. [130]Kara E, Ling H, Pittman AM, Shaw K, de Silva R, Simone R, The MAPT p.A152T variant is a risk factor associated with tauopathies with atypical clinical and neuropathological features. Neurobiol Aging 2012; 33: 2231.e7– 2231.e14. PMC3657164 22595371
  110. [131]Grover A, England E, Baker M, Sahara N, Adamson J, Granger B, A novel tau mutation in exon 9 (I260V) causes a four-repeat tauopathy. Exp Neurol 2003; 184: 131– 40. 14637086
  111. [132]Pickering-Brown S, Baker M, Yen SH, Liu WK, Hasegawa M, Cairns N, Pick’s disease is associated with mutations in the tau gene. Ann Neurol 2000; 48: 859– 67. 11117542
  112. [133]Hogg M, Grujic ZM, Baker M, Demirci S, Guillozet AL, Sweet AP, The L266V tau mutation is associated with frontotemporal dementia and Pick-like 3R and 4R tauopathy. Acta Neuropathol 2003; 106: 323– 36. 12883828
  113. [134]Kobayashi T, Ota S, Tanaka K, Ito Y, Hasegawa M, Umeda Y, A novel L266V mutation of the tau gene causes frontotemporal dementia with a unique tau pathology. Ann Neurol 2003; 53: 133– 7. 12509859
  114. [135]Barghorn S, Zheng-Fischhofer Q, Ackmann M, Biernat J, Von Bergen M, Mandelkow EM, Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 2000; 39: 11714– 21. 10995239
  115. [136]Bronner IF, Ter Meulen BC, Azmani A, Severijnen LA, Willemsen R, Kamphorst W, Hereditary Pick’s disease with the G272V tau mutation shows predominant three-repeat tau pathology. Brain 2005; 128: 2645– 53. 16014652
  116. [137]Hasegawa M, Smith MJ, Iijima M, Tabira T, Goedert M. FTDP-17 mutations N279K and S305N in tau produce increased splicing of exon 10. FEBS Lett 1999; 443: 93– 6. 9989582
  117. [138]D’Souza I, Poorkaj P, Hong M, Nochlin D, Lee VM, Bird TD, Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc Natl Acad Sci U S A 1999; 96: 5598– 603. 10318930 PMC21906
  118. [139]Wren MC, Zhao J, Liu C-C, Murray ME, Atagi Y, Davis MD, Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells. Mol Neurodegener 2015; 10: 46. 26373282 PMC4572645
  119. [140]Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 1998; 282: 1914– 7. 9836646
  120. [141]Goedert M, Jakes R, Crowther RA. Effects of frontotemporal dementia FTDP-17 mutations on heparin-induced assembly of tau filaments. FEBS Lett 1999; 450: 306– 11. 10359094
  121. [142]Rizzu P, Van Swieten JC, Joosse M, Hasegawa M, Stevens M, Tibben A, High prevalence of mutations in the microtubule-associated protein tau in a population study of frontotemporal dementia in the Netherlands. Am J Hum Genet 1999; 64: 414– 21. 9973279 PMC1377751
  122. [143]Von Bergen M, Barghorn S, Li L, Marx A, Biernat J, Mandelkow EM, Mutations of tau protein in frontotemporal dementia promote aggregation of paired helical filaments by enhancing local β-structure. J Biol Chem 2001; 276: 48165– 74. 11606569
  123. [144]Yoshida H, Crowther RA, Goedert M. Functional effects of tau gene mutations deltaN296 and N296H. J Neurochem 2002; 80: 548– 51. 11906000
  124. [145]Grover A, DeTure M, Yen SH, Hutton M. Effects on splicing and protein function of three mutations in codon N296 of tau in vitro. Neurosci Lett 2002; 323: 33– 6. 11911984
  125. [146]Iovino M, Pfisterer U, Holton JL, Lashley T, Swingler RJ, Calo L, The novel MAPT mutation K298E: Mechanisms of mutant tau toxicity, brain pathology and tau expression in induced fibroblast-derived neurons. Acta Neuropathol 2014; 127: 283– 95. 24292008 PMC3895181
  126. [147]Nacharaju P, Lewis J, Easson C, Yen S, Hackett J, Hutton M, Accelerated filament formation from tau protein with specific FTDP-17 missense mutations. FEBS Lett 1999; 447: 195– 9. 10214944
  127. [148]Hasegawa M, Smith MJ, Goedert M. Tau proteins with FTDP-17 mutations have a reduced ability to promote microtubule assembly. FEBS Lett 1998; 437: 207– 10. 9824291
  128. [149]Dayanandan R, Van Slegtenhorst M, Mack TGA, Ko L, Yen SH, Leroy K, Mutations in tau reduce its microtubule binding properties in intact cells and affect its phosphorylation. FEBS Lett 1999; 446: 228– 32. 10100846
  129. [150]Elbaum-garfinkle S, Cobb G, Compton JT, Li X-H, Rhoades E. Tau mutants bind tubulin heterodimers with enhanced affinity. Proc Natl Acad Sci U S A 2014; 111: 6311– 6. 24733915 PMC4035965
  130. [151]Brandt R, Hundelt M, Shahani N. Tau alteration and neuronal degeneration in tauopathies: Mechanisms and models. Biochim Biophys Acta - Mol Basis Dis 2005; 1739: 331– 54. 15615650
  131. [152]Bugiani O, Murrell JR, Giaccone G, Hasegawa M, Ghigo G, Tabaton M, Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 1999; 58: 667– 77. 10374757
  132. [153]Lladó A, Ezquerra M, Sánchez-Valle R, Rami L, Tolosa E, Molinuevo JL. A novel MAPT mutation (P301T) associated with familial frontotemporal dementia. Eur J Neurol 2007; 14: 9– 10. 17662000
  133. [154]Ros R, Thobois S, Streichenberger N, Kopp N, Sánchez MP, Pérez M, A new mutation of the τ gene, G303V, in early-onset familial progressive supranuclear palsy. Arch Neurol 2005; 62: 1444– 50. 16157753
  134. [155]Kovacs GG, Pittman A, Revesz T, Luk C, Lees A, Kiss E, MAPT S305I mutation: Implications for argyrophilic grain disease. Acta Neuropathol 2008; 116: 103– 18. 18066559
  135. [156]Iijima M, Tabira T, Poorkaj P, Schellenberg GD, Trojanowski JQ, Lee VMY, A distinct familial presenile dementia with a novel missense mutation in the tau gene. Neuroreport 1999; 10: 497– 501. 10208578
  136. [157]Van Herpen E, Rosso SM, Serverijnen LA, Yoshida H, Breedveld G, Van De Graaf R, Variable phenotypic expression and extensive tau pathology in two families with the novel tau mutation L315R. Ann Neurol 2003; 54: 573– 81. 14595646
  137. [158]Zarranz JJ, Ferrer I, Lezcano E, Forcadas MI, Eizaguirre B, Atarés B, A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease. Neurology 2005; 64: 1578– 85. 15883319
  138. [159]Tacik P, DeTure M, Lin WL, Sanchez Contreras M, Wojtas A, Hinkle KM, A novel tau mutation, p.K317N, causes globular glial tauopathy. Acta Neuropathol 2015; 130: 199– 214. 25900293 PMC5039015
  139. [160]Deramecourt V, Lebert F, Maurage CA, Fernandez-Gomez FJ, Dujardin S, Colin M, Clinical, neuropathological, and biochemical characterization of the novel tau mutation P332S. J Alzheimer’s Dis 2012; 31: 741– 9. 22699846
  140. [161]Spina S, Murrell JR, Yoshida H, Ghetti B, Bermingham N, Sweeney B, The novel Tau mutation G335S: Clinical, neuropathological and molecular characterization. Acta Neuropathol 2007; 113: 461– 70. 17186252
  141. [162]Neumann M, Diekmann S, Bertsch U, Vanmassenhove B, Bogerts B, Kretzschmar HA. Novel G335V mutation in the tau gene associated with early onset familial frontotemporal dementia. Neurogenetics 2005; 6: 91– 5. 15765246
  142. [163]Deture M, Ko LW, Yen S, Nacharaju P, Easson C, Lewis J, Missense tau mutations identified in FTDP-17 have a small effect on tau-microtubule interactions. Brain Res 2000; 853: 5– 14. 10627302
  143. [164]Spillantini MG, Crowther RA, Goedert M. Comparison of the neurofibrillary pathology in Alzheimer’s disease and familial presenile dementia with tangles. Acta Neuropathol 1996; 92: 42– 8. 8811124
  144. [165]Lippa CF, Zhukareva V, Kawarai T, Uryu K, Shafiq M, Nee LE, Frontotemporal dementia with novel tau pathology and a Glu342Val tau mutation. Ann Neurol 2000; 48: 850– 8. 11117541
  145. [166]Nicholl DJ, Greenstone MA, Clarke CE, Rizzu P, Crooks D, Crowe A, An English Kindred with a Novel Recessive Tauopathy and Respiratory Failure. Ann Neurol 2003; 54: 682– 6. 14595660
  146. [167]Momeni P, Wickremaratchi MM, Bell J, Arnold R, Beer R, Hardy J, Familial early onset frontotemporal dementia caused by a novel S356T MAPT mutation, initially diagnosed as schizophrenia. Clin Neurol Neurosurg 2010; 112: 917– 20. 20708332
  147. [168]Rossi G, Bastone A, Piccoli E, Mazzoleni G, Morbin M, Uggetti A, New mutations in MAPT gene causing frontotemporal lobar degeneration: Biochemical and structural characterization. Neurobiol Aging 2012; 33: 834.e1– 834.e6. 21943955
  148. [169]Popović M, Fabjan A, Mraz J, Magdič J, Glavač D, Zupan A, Tau protein mutation P364S in two sisters: Clinical course and neuropathology with emphasis on new, composite neuronal tau inclusions. Acta Neuropathol 2014; 128: 155– 7. 24821615
  149. [170]Neumann M, Schulz-Schaeffer W, Crowther RA, Smith MJ, Spillantini MG, Goedert M, Pick’s disease associated with the novel Tau gene mutation K369I. Ann Neurol 2001; 50: 503– 13. 11601501
  150. [171]Tacik P, DeTure MA, Carlomagno Y, Lin WL, Murray ME, Baker MC, FTDP-17 with Pick body-like inclusions associated with a novel tau mutation, p.E372G. Brain Pathol 2017; 27: 612– 26. 27529406 PMC5380645
  151. [172]Ghetti B, Murrell JR, Zolo P, Spillantini MG, Goedert M. Progress in hereditary tauopathies: A mutation in the Tau gene (G389R) causes a pick disease-like syndrome. Ann N Y Acad Sci 2000; 920: 52– 62. 11193177
  152. [173]Murrell JR, Spillantini MG, Zolo P, Guazzelli M, Smith MJ, Hasegawa M, Tau gene mutation G389R causes a tauopathy with abundant pick body-like inclusions and axonal deposits. J Neuropathol Exp Neurol 1999; 58: 1207– 26. 10604746
  153. [174]Santa-Maria I, Varghese M, Ksiezak-Reding H, Dzhun A, Wang J, Pasinetti GM. Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of tau protein in aggresomes. J Biol Chem 2012; 287: 20522– 33. 22496370 PMC3370237
  154. [175]Guo JL, Covell DJ, Daniels JP, Iba M, Stieber A, Zhang B, Distinct α-synuclein strains differentially promote tau inclusions in neurons. Cell 2013; 154: 103– 17. 23827677 PMC3820001
  155. [176]Mirbaha H, Holmes BB, Sanders DW, Bieschke J, Diamond MI. Tau trimers are the minimal propagation unit spontaneously internalized to seed intracellular aggregation. J Biol Chem 2015; 290: 14893– 903. 25887395 PMC4463437
  156. [177]Audouard E, Houben S, Masaracchia C, Yilmaz Z, Suain V, Authelet M, High molecular-weight paired helical filaments from Alzheimer brain induces seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am J Pathol 2016; 186: 2709– 22. 27497324
  157. [178]Furman JL, Vaquer-Alicea J, White CL, Cairns NJ, Nelson PT, Diamond MI. Widespread tau seeding activity at early Braak stages. Acta Neuropathol 2017; 133: 91– 100. 27878366 PMC5833300
  158. [179]Kaufman SK, Thomas TL, Del Tredici K, Braak H, Diamond MI. Characterization of tau prion seeding activity and strains from formaldehyde-fixed tissue. Acta Neuropathol Commun 2017; 5: 41. 28587664 PMC5461712
  159. [181]Clavaguera F, Hench J, Lavenir I, Schweighauser G, Frank S, Goedert M, Peripheral administration of tau aggregates triggers intracerebral tauopathy in transgenic mice. Acta Neuropathol 2014; 127: 299– 301. 24362441 PMC4253855
  160. [182]Gibbons XGS, Banks RA, Kim B, Xu H, Changolkar L, Leight SN, GFP-mutant human tau transgenic mice develop tauopathy following CNS injections of Alzheimer’s brain-derived pathological tau or synthetic mutant human tau fibrils. J Neurosci 2017; 37: 11485– 94. 28986461 PMC5700428
  161. [183]Narasimhan XS, Guo JL, Changolkar L, Stieber A, Mcbride XD, Silva LV, Pathological tau strains from human brains recapitulate the diversity of tauopathies in nontransgenic mouse brain. J Neurosci 2017; 37: 11406– 23. 29054878 PMC5700423

Cited by

Sorted by citations

Authors
Strang, K. H., Golde, T. E., & Giasson, B. I.
Affiliations
University of Florida Health (US)
Corresponding author
Giasson, Benoit I.
ORCID
Venue
Laboratory Investigation
Publisher
Elsevier BV
Published
2019-07
Volume
99
Issue
7
Pages
912-928
ISSN
0023-6837 (ISSN-L)
DOI
10.1038/s41374-019-0197-x
PMC
PMC7289372
OpenAlex
W2914613198
Cited by
424
References
25
Citations by year
2026: 71 · 2025: 86 · 2024: 70 · 2023: 58 · 2022: 57 · 2021: 43 · 2020: 31 · 2019: 6 · 2014: 1
FWCI
4.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Laboratory Investigation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Florida Department of Health (7AZ25)
  • U.S. Department of Health & Human Services | National Institutes of Health (R01NS089022)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
MAPT mutations, tauopathy, tau aggregation, neurodegeneration, frontotemporal dementia with parkinsonism linked to chromosome 17, prion-like propagation, Alzheimer's disease
MeSH terms
Animals, Humans, Microtubules, Mutation, Protein Processing, Post-Translational, tau Proteins, Protein Splicing, Parkinsonian Disorders, Tauopathies, Protein Aggregation, Pathological

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review