Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration
Abstract
:1. Introduction
2. Structural Variants of Tau
3. Tau Aggregation in Tauopathies
4. Tau Expression in Oligodendrocytes
4.1. Tau and Oligodendrocytes in Diseased Brains: Perspective from Animal Studies
4.2. Oligodendrocyte Dysfunction in Human Tauopathy
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
- Weingarten, M.D.; Lockwood, A.H.; Hwo, S.Y.; Kirschner, M.W. A protein factor essential for microtubule assembly. Proc. Natl. Acad. Sci. USA 1975, 72, 1858–1862. [Google Scholar] [CrossRef]
- Brion, J.P.; Couck, A.M.; Passareiro, E.; Flament-Durand, J. Neurofibrillary tangles of Alzheimer’s disease: An immunohistochemical study. J. Submicrosc. Cytol. 1985, 17, 89–96. [Google Scholar]
- Delacourte, A.; Defossez, A. Alzheimer’s disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J. Neurol. Sci. 1986, 76, 173–186. [Google Scholar] [CrossRef]
- Goedert, M.; Wischik, C.M.; Crowther, R.A.; Walker, J.E.; Klug, A. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: Identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci. USA 1988, 85, 4051–4055. [Google Scholar] [CrossRef]
- Grundke-Iqbal, I.; Iqbal, K.; Quinlan, M.; Tung, Y.C.; Zaidi, M.S.; Wisniewski, H.M. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 1986, 261, 6084–6089. [Google Scholar] [CrossRef]
- Grundke-Iqbal, I.; Vorbrodt, A.W.; Iqbal, K.; Tung, Y.C.; Wang, G.P.; Wisniewski, H.M. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res. 1988, 464, 43–52. [Google Scholar] [CrossRef]
- Kondo, J.; Honda, T.; Mori, H.; Hamada, Y.; Miura, R.; Ogawara, M.; Ihara, Y. The carboxyl third of tau is tightly bound to paired helical filaments. Neuron 1988, 1, 827–834. [Google Scholar] [CrossRef]
- Hutton, M.; Lendon, C.L.; Rizzu, P.; Baker, M.; Froelich, S.; Houlden, H.; Pickering-Brown, S.; Chakraverty, S.; Isaacs, A.; Grover, A.; et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998, 393, 702–705. [Google Scholar] [CrossRef]
- Poorkaj, P.; Bird, T.D.; Wijsman, E.; Nemens, E.; Garruto, R.M.; Anderson, L.; Andreadis, A.; Wiederholt, W.C.; Raskind, M.; Schellenberg, G.D. Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann. Neurol. 1998, 43, 815–825. [Google Scholar] [CrossRef]
- Spillantini, M.G.; Murrell, J.R.; Goedert, M.; Farlow, M.R.; Klug, A.; Ghetti, B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc. Natl. Acad. Sci. USA 1998, 95, 7737–7741. [Google Scholar] [CrossRef]
- Spillantini, M.G.; Bird, T.D.; Ghetti, B. Frontotemporal dementia and Parkinsonism linked to chromosome 17: A new group of tauopathies. Brain Pathol. 1998, 8, 387–402. [Google Scholar] [CrossRef]
- Yoshiyama, Y.; Higuchi, M.; Zhang, B.; Huang, S.M.; Iwata, N.; Saido, T.C.; Maeda, J.; Suhara, T.; Trojanowski, J.Q.; Lee, V.M. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 2007, 53, 337–351. [Google Scholar] [CrossRef]
- Oddo, S.; Caccamo, A.; Shepherd, J.D.; Murphy, M.P.; Golde, T.E.; Kayed, R.; Metherate, R.; Mattson, M.P.; Akbari, Y.; LaFerla, F.M. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: Intracellular Abeta and synaptic dysfunction. Neuron 2003, 39, 409–421. [Google Scholar] [CrossRef]
- Ramsden, M.; Kotilinek, L.; Forster, C.; Paulson, J.; McGowan, E.; SantaCruz, K.; Guimaraes, A.; Yue, M.; Lewis, J.; Carlson, G.; et al. Age-dependent neurofibrillary tangle formation, neuron loss, and memory impairment in a mouse model of human tauopathy (P301L). J. Neurosci. 2005, 25, 10637–10647. [Google Scholar] [CrossRef]
- Wang, C.; Fan, L.; Khawaja, R.R.; Liu, B.; Zhan, L.; Kodama, L.; Chin, M.; Li, Y.; Le, D.; Zhou, Y.; et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat. Commun. 2022, 13, 1969. [Google Scholar] [CrossRef]
- Asai, H.; Ikezu, S.; Tsunoda, S.; Medalla, M.; Luebke, J.; Haydar, T.; Wolozin, B.; Butovsky, O.; Kugler, S.; Ikezu, T. Depletion of microglia and inhibition of exosome synthesis halt tau propagation. Nat. Neurosci. 2015, 18, 1584–1593. [Google Scholar] [CrossRef]
- Braak, H.; Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991, 82, 239–259. [Google Scholar] [CrossRef]
- Braak, H.; Braak, E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol. Aging 1995, 16, 271–278; discussion 278–284. [Google Scholar] [CrossRef]
- Seeley, W.W. Frontotemporal dementia neuroimaging: A guide for clinicians. Front. Neurol. Neurosci. 2009, 24, 160–167. [Google Scholar] [CrossRef]
- Price, J.L.; Ko, A.I.; Wade, M.J.; Tsou, S.K.; McKeel, D.W.; Morris, J.C. Neuron number in the entorhinal cortex and CA1 in preclinical Alzheimer disease. Arch. Neurol. 2001, 58, 1395–1402. [Google Scholar] [CrossRef]
- Hoenig, M.C.; Bischof, G.N.; Seemiller, J.; Hammes, J.; Kukolja, J.; Onur, O.A.; Jessen, F.; Fliessbach, K.; Neumaier, B.; Fink, G.R.; et al. Networks of tau distribution in Alzheimer’s disease. Brain 2018, 141, 568–581. [Google Scholar] [CrossRef]
- Medina, M. An Overview on the Clinical Development of Tau-Based Therapeutics. Int. J. Mol. Sci. 2018, 19, 1160. [Google Scholar] [CrossRef]
- Jadhav, S.; Avila, J.; Scholl, M.; Kovacs, G.G.; Kovari, E.; Skrabana, R.; Evans, L.D.; Kontsekova, E.; Malawska, B.; de Silva, R.; et al. A walk through tau therapeutic strategies. Acta Neuropathol. Commun. 2019, 7, 22. [Google Scholar] [CrossRef]
- Hoskin, J.L.; Sabbagh, M.N.; Al-Hasan, Y.; Decourt, B. Tau immunotherapies for Alzheimer’s disease. Expert Opin. Investig. Drugs 2019, 28, 545–554. [Google Scholar] [CrossRef]
- Neve, R.L.; Harris, P.; Kosik, K.S.; Kurnit, D.M.; Donlon, T.A. Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Brain Res. 1986, 387, 271–280. [Google Scholar] [CrossRef]
- Andreadis, A. Misregulation of tau alternative splicing in neurodegeneration and dementia. Prog. Mol. Subcell. Biol. 2006, 44, 89–107. [Google Scholar] [CrossRef]
- Wang, Y.; Mandelkow, E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016, 17, 5–21. [Google Scholar] [CrossRef]
- Mandelkow, E.M.; Schweers, O.; Drewes, G.; Biernat, J.; Gustke, N.; Trinczek, B.; Mandelkow, E. Structure, microtubule interactions, and phosphorylation of tau protein. Ann. N. Y. Acad. Sci. 1996, 777, 96–106. [Google Scholar] [CrossRef]
- Goedert, M.; Spillantini, M.G.; Jakes, R.; Rutherford, D.; Crowther, R.A. Multiple isoforms of human microtubule-associated protein tau: Sequences and localization in neurofibrillary tangles of Alzheimer’s disease. Neuron 1989, 3, 519–526. [Google Scholar] [CrossRef]
- Goedert, M. Tau filaments in neurodegenerative diseases. FEBS Lett. 2018, 592, 2383–2391. [Google Scholar] [CrossRef]
- Brandt, R.; Leger, J.; Lee, G. Interaction of tau with the neural plasma membrane mediated by tau’s amino-terminal projection domain. J. Cell Biol. 1995, 131, 1327–1340. [Google Scholar] [CrossRef]
- Lee, G.; Newman, S.T.; Gard, D.L.; Band, H.; Panchamoorthy, G. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 1998, 111 Pt 21, 3167–3177. [Google Scholar] [CrossRef]
- Ennulat, D.J.; Liem, R.K.; Hashim, G.A.; Shelanski, M.L. Two separate 18-amino acid domains of tau promote the polymerization of tubulin. J. Biol. Chem. 1989, 264, 5327–5330. [Google Scholar] [CrossRef]
- Lee, G.; Neve, R.L.; Kosik, K.S. The microtubule binding domain of tau protein. Neuron 1989, 2, 1615–1624. [Google Scholar] [CrossRef]
- Goedert, M.; Jakes, R. Expression of separate isoforms of human tau protein: Correlation with the tau pattern in brain and effects on tubulin polymerization. EMBO J. 1990, 9, 4225–4230. [Google Scholar] [CrossRef]
- Kosik, K.S.; Orecchio, L.D.; Bakalis, S.; Neve, R.L. Developmentally regulated expression of specific tau sequences. Neuron 1989, 2, 1389–1397. [Google Scholar] [CrossRef]
- Takuma, H.; Arawaka, S.; Mori, H. Isoforms changes of tau protein during development in various species. Brain Res. Dev. Brain Res. 2003, 142, 121–127. [Google Scholar] [CrossRef]
- Goedert, M.; Spillantini, M.G.; Crowther, R.A. Cloning of a big tau microtubule-associated protein characteristic of the peripheral nervous system. Proc. Natl. Acad. Sci. USA 1992, 89, 1983–1987. [Google Scholar] [CrossRef]
- Couchie, D.; Mavilia, C.; Georgieff, I.S.; Liem, R.K.; Shelanski, M.L.; Nunez, J. Primary structure of high molecular weight tau present in the peripheral nervous system. Proc. Natl. Acad. Sci. USA 1992, 89, 4378–4381. [Google Scholar] [CrossRef]
- Kopke, E.; Tung, Y.C.; Shaikh, S.; Alonso, A.C.; Iqbal, K.; Grundke-Iqbal, I. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J. Biol. Chem. 1993, 268, 24374–24384. [Google Scholar] [CrossRef]
- Hanger, D.P.; Seereeram, A.; Noble, W. Mediators of tau phosphorylation in the pathogenesis of Alzheimer’s disease. Expert. Rev. Neurother. 2009, 9, 1647–1666. [Google Scholar] [CrossRef]
- Lee, G. Tau and src family tyrosine kinases. Biochim. Biophys. Acta 2005, 1739, 323–330. [Google Scholar] [CrossRef]
- Yu, Y.; Run, X.; Liang, Z.; Li, Y.; Liu, F.; Liu, Y.; Iqbal, K.; Grundke-Iqbal, I.; Gong, C.X. Developmental regulation of tau phosphorylation, tau kinases, and tau phosphatases. J. Neurochem. 2009, 108, 1480–1494. [Google Scholar] [CrossRef]
- Hisanaga, S.I.; Krishnankutty, A.; Kimura, T. In vivo analysis of the phosphorylation of tau and the tau protein kinases Cdk5-p35 and GSK3beta by using Phos-tag SDS-PAGE. J. Proteom. 2022, 262, 104591. [Google Scholar] [CrossRef]
- Christensen, K.R.; Combs, B.; Richards, C.; Grabinski, T.; Alhadidy, M.M.; Kanaan, N.M. Phosphomimetics at Ser199/Ser202/Thr205 in Tau Impairs Axonal Transport in Rat Hippocampal Neurons. Mol. Neurobiol. 2023, 60, 3423–3438. [Google Scholar] [CrossRef]
- Neddens, J.; Temmel, M.; Flunkert, S.; Kerschbaumer, B.; Hoeller, C.; Loeffler, T.; Niederkofler, V.; Daum, G.; Attems, J.; Hutter-Paier, B. Phosphorylation of different tau sites during progression of Alzheimer’s disease. Acta Neuropathol. Commun. 2018, 6, 52. [Google Scholar] [CrossRef]
- Guillozet-Bongaarts, A.L.; Cahill, M.E.; Cryns, V.L.; Reynolds, M.R.; Berry, R.W.; Binder, L.I. Pseudophosphorylation of tau at serine 422 inhibits caspase cleavage: In vitro evidence and implications for tangle formation in vivo. J. Neurochem. 2006, 97, 1005–1014. [Google Scholar] [CrossRef]
- Min, S.W.; Cho, S.H.; Zhou, Y.; Schroeder, S.; Haroutunian, V.; Seeley, W.W.; Huang, E.J.; Shen, Y.; Masliah, E.; Mukherjee, C.; et al. Acetylation of tau inhibits its degradation and contributes to tauopathy. Neuron 2010, 67, 953–966. [Google Scholar] [CrossRef]
- Cook, C.; Carlomagno, Y.; Gendron, T.F.; Dunmore, J.; Scheffel, K.; Stetler, C.; Davis, M.; Dickson, D.; Jarpe, M.; DeTure, M.; et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum. Mol. Genet. 2014, 23, 104–116. [Google Scholar] [CrossRef]
- Kamah, A.; Huvent, I.; Cantrelle, F.X.; Qi, H.; Lippens, G.; Landrieu, I.; Smet-Nocca, C. Nuclear magnetic resonance analysis of the acetylation pattern of the neuronal Tau protein. Biochemistry 2014, 53, 3020–3032. [Google Scholar] [CrossRef]
- Noack, M.; Leyk, J.; Richter-Landsberg, C. HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. Glia 2014, 62, 535–547. [Google Scholar] [CrossRef]
- Irwin, D.J.; Cohen, T.J.; Grossman, M.; Arnold, S.E.; McCarty-Wood, E.; Van Deerlin, V.M.; Lee, V.M.; Trojanowski, J.Q. Acetylated tau neuropathology in sporadic and hereditary tauopathies. Am. J. Pathol. 2013, 183, 344–351. [Google Scholar] [CrossRef]
- Min, S.W.; Sohn, P.D.; Li, Y.; Devidze, N.; Johnson, J.R.; Krogan, N.J.; Masliah, E.; Mok, S.A.; Gestwicki, J.E.; Gan, L. SIRT1 Deacetylates Tau and Reduces Pathogenic Tau Spread in a Mouse Model of Tauopathy. J. Neurosci. 2018, 38, 3680–3688. [Google Scholar] [CrossRef]
- Puangmalai, N.; Sengupta, U.; Bhatt, N.; Gaikwad, S.; Montalbano, M.; Bhuyan, A.; Garcia, S.; McAllen, S.; Sonawane, M.; Jerez, C.; et al. Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer’s disease. J. Biol. Chem. 2022, 298, 101766. [Google Scholar] [CrossRef]
- Reyes, J.F.; Fu, Y.; Vana, L.; Kanaan, N.M.; Binder, L.I. Tyrosine nitration within the proline-rich region of Tau in Alzheimer’s disease. Am. J. Pathol. 2011, 178, 2275–2285. [Google Scholar] [CrossRef]
- Reyes, J.F.; Geula, C.; Vana, L.; Binder, L.I. Selective tau tyrosine nitration in non-AD tauopathies. Acta Neuropathol. 2012, 123, 119–132. [Google Scholar] [CrossRef]
- Alquezar, C.; Arya, S.; Kao, A.W. Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation. Front. Neurol. 2020, 11, 595532. [Google Scholar] [CrossRef]
- Zhang, Y.J.; Xu, Y.F.; Chen, X.Q.; Wang, X.C.; Wang, J.Z. Nitration and oligomerization of tau induced by peroxynitrite inhibit its microtubule-binding activity. FEBS Lett. 2005, 579, 2421–2427. [Google Scholar] [CrossRef]
- Horiguchi, T.; Uryu, K.; Giasson, B.I.; Ischiropoulos, H.; LightFoot, R.; Bellmann, C.; Richter-Landsberg, C.; Lee, V.M.; Trojanowski, J.Q. Nitration of tau protein is linked to neurodegeneration in tauopathies. Am. J. Pathol. 2003, 163, 1021–1031. [Google Scholar] [CrossRef]
- Morris, M.; Knudsen, G.M.; Maeda, S.; Trinidad, J.C.; Ioanoviciu, A.; Burlingame, A.L.; Mucke, L. Tau post-translational modifications in wild-type and human amyloid precursor protein transgenic mice. Nat. Neurosci. 2015, 18, 1183–1189. [Google Scholar] [CrossRef]
- Babu, J.R.; Geetha, T.; Wooten, M.W. Sequestosome 1/p62 shuttles polyubiquitinated tau for proteasomal degradation. J. Neurochem. 2005, 94, 192–203. [Google Scholar] [CrossRef] [PubMed]
- Flach, K.; Ramminger, E.; Hilbrich, I.; Arsalan-Werner, A.; Albrecht, F.; Herrmann, L.; Goedert, M.; Arendt, T.; Holzer, M. Axotrophin/MARCH7 acts as an E3 ubiquitin ligase and ubiquitinates tau protein in vitro impairing microtubule binding. Biochim. Biophys. Acta 2014, 1842, 1527–1538. [Google Scholar] [CrossRef] [PubMed]
- Petrucelli, L.; Dickson, D.; Kehoe, K.; Taylor, J.; Snyder, H.; Grover, A.; De Lucia, M.; McGowan, E.; Lewis, J.; Prihar, G.; et al. CHIP and Hsp70 regulate tau ubiquitination, degradation and aggregation. Hum. Mol. Genet. 2004, 13, 703–714. [Google Scholar] [CrossRef] [PubMed]
- Dickey, C.A.; Kamal, A.; Lundgren, K.; Klosak, N.; Bailey, R.M.; Dunmore, J.; Ash, P.; Shoraka, S.; Zlatkovic, J.; Eckman, C.B.; et al. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J. Clin. Investig. 2007, 117, 648–658. [Google Scholar] [CrossRef] [PubMed]
- Luo, H.B.; Xia, Y.Y.; Shu, X.J.; Liu, Z.C.; Feng, Y.; Liu, X.H.; Yu, G.; Yin, G.; Xiong, Y.S.; Zeng, K.; et al. SUMOylation at K340 inhibits tau degradation through deregulating its phosphorylation and ubiquitination. Proc. Natl. Acad. Sci. USA 2014, 111, 16586–16591. [Google Scholar] [CrossRef]
- Hernandez, I.; Luna, G.; Rauch, J.N.; Reis, S.A.; Giroux, M.; Karch, C.M.; Boctor, D.; Sibih, Y.E.; Storm, N.J.; Diaz, A.; et al. A farnesyltransferase inhibitor activates lysosomes and reduces tau pathology in mice with tauopathy. Sci. Transl. Med. 2019, 11, eaat3005. [Google Scholar] [CrossRef] [PubMed]
- Dorval, V.; Fraser, P.E. Small ubiquitin-like modifier (SUMO) modification of natively unfolded proteins tau and alpha-synuclein. J. Biol. Chem. 2006, 281, 9919–9924. [Google Scholar] [CrossRef] [PubMed]
- Arnold, C.S.; Johnson, G.V.; Cole, R.N.; Dong, D.L.; Lee, M.; Hart, G.W. The microtubule-associated protein tau is extensively modified with O-linked N-acetylglucosamine. J. Biol. Chem. 1996, 271, 28741–28744. [Google Scholar] [CrossRef] [PubMed]
- Yuzwa, S.A.; Shan, X.; Macauley, M.S.; Clark, T.; Skorobogatko, Y.; Vosseller, K.; Vocadlo, D.J. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 2012, 8, 393–399. [Google Scholar] [CrossRef]
- Lu, S.; Yin, X.; Wang, J.; Gu, Q.; Huang, Q.; Jin, N.; Chu, D.; Xu, Z.; Liu, F.; Qian, W. SIRT1 regulates O-GlcNAcylation of tau through OGT. Aging 2020, 12, 7042–7055. [Google Scholar] [CrossRef]
- Gong, C.X.; Liu, F.; Iqbal, K. O-GlcNAcylation: A regulator of tau pathology and neurodegeneration. Alzheimer’s Dement. 2016, 12, 1078–1089. [Google Scholar] [CrossRef]
- Quinn, J.P.; Corbett, N.J.; Kellett, K.A.B.; Hooper, N.M. Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers. J. Alzheimer’s Dis. 2018, 63, 13–33. [Google Scholar] [CrossRef] [PubMed]
- Xia, Y.; Lloyd, G.M.; Giasson, B.I. Targeted proteolytic products of tau and alpha-synuclein in neurodegeneration. Essays Biochem. 2021, 65, 905–912. [Google Scholar] [CrossRef] [PubMed]
- Cohen, T.J.; Constance, B.H.; Hwang, A.W.; James, M.; Yuan, C.X. Intrinsic Tau Acetylation Is Coupled to Auto-Proteolytic Tau Fragmentation. PLoS ONE 2016, 11, e0158470. [Google Scholar] [CrossRef] [PubMed]
- Garg, S.; Timm, T.; Mandelkow, E.M.; Mandelkow, E.; Wang, Y. Cleavage of Tau by calpain in Alzheimer’s disease: The quest for the toxic 17 kD fragment. Neurobiol. Aging 2011, 32, 1–14. [Google Scholar] [CrossRef] [PubMed]
- Zhao, X.; Kotilinek, L.A.; Smith, B.; Hlynialuk, C.; Zahs, K.; Ramsden, M.; Cleary, J.; Ashe, K.H. Caspase-2 cleavage of tau reversibly impairs memory. Nat. Med. 2016, 22, 1268–1276. [Google Scholar] [CrossRef]
- Noel, A.; Foveau, B.; LeBlanc, A.C. Caspase-6-cleaved Tau fails to induce Tau hyperphosphorylation and aggregation, neurodegeneration, glial inflammation, and cognitive deficits. Cell Death Dis. 2021, 12, 227. [Google Scholar] [CrossRef] [PubMed]
- Ukmar-Godec, T.; Fang, P.; Ibanez de Opakua, A.; Henneberg, F.; Godec, A.; Pan, K.T.; Cima-Omori, M.S.; Chari, A.; Mandelkow, E.; Urlaub, H.; et al. Proteasomal degradation of the intrinsically disordered protein tau at single-residue resolution. Sci. Adv. 2020, 6, eaba3916. [Google Scholar] [CrossRef] [PubMed]
- Schlegel, K.; Awwad, K.; Heym, R.G.; Holzinger, D.; Doell, A.; Barghorn, S.; Jahn, T.R.; Klein, C.; Mordashova, Y.; Schulz, M.; et al. N368-Tau fragments generated by legumain are detected only in trace amount in the insoluble Tau aggregates isolated from AD brain. Acta Neuropathol. Commun. 2019, 7, 177. [Google Scholar] [CrossRef] [PubMed]
- Gu, J.; Xu, W.; Jin, N.; Li, L.; Zhou, Y.; Chu, D.; Gong, C.X.; Iqbal, K.; Liu, F. Truncation of Tau selectively facilitates its pathological activities. J. Biol. Chem. 2020, 295, 13812–13828. [Google Scholar] [CrossRef]
- Strang, K.H.; Golde, T.E.; Giasson, B.I. MAPT mutations, tauopathy, and mechanisms of neurodegeneration. Lab. Investig. 2019, 99, 912–928. [Google Scholar] [CrossRef]
- Crary, J.F.; Trojanowski, J.Q.; Schneider, J.A.; Abisambra, J.F.; Abner, E.L.; Alafuzoff, I.; Arnold, S.E.; Attems, J.; Beach, T.G.; Bigio, E.H.; et al. Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol. 2014, 128, 755–766. [Google Scholar] [CrossRef]
- Kim, D.; Kim, H.S.; Choi, S.M.; Kim, B.C.; Lee, M.C.; Lee, K.H.; Lee, J.H. Primary Age-Related Tauopathy: An Elderly Brain Pathology Frequently Encountered during Autopsy. J. Pathol. Transl. Med. 2019, 53, 159–163. [Google Scholar] [CrossRef]
- Bronner, I.F.; ter Meulen, B.C.; Azmani, A.; Severijnen, L.A.; Willemsen, R.; Kamphorst, W.; Ravid, R.; Heutink, P.; van Swieten, J.C. Hereditary Pick’s disease with the G272V tau mutation shows predominant three-repeat tau pathology. Brain 2005, 128, 2645–2653. [Google Scholar] [CrossRef]
- Barghorn, S.; Zheng-Fischhofer, Q.; Ackmann, M.; Biernat, J.; von Bergen, M.; Mandelkow, E.M.; Mandelkow, E. Structure, microtubule interactions, and paired helical filament aggregation by tau mutants of frontotemporal dementias. Biochemistry 2000, 39, 11714–11721. [Google Scholar] [CrossRef]
- Hong, M.; Zhukareva, V.; Vogelsberg-Ragaglia, V.; Wszolek, Z.; Reed, L.; Miller, B.I.; Geschwind, D.H.; Bird, T.D.; McKeel, D.; Goate, A.; et al. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science 1998, 282, 1914–1917. [Google Scholar] [CrossRef]
- Fitzpatrick, A.W.P.; Falcon, B.; He, S.; Murzin, A.G.; Murshudov, G.; Garringer, H.J.; Crowther, R.A.; Ghetti, B.; Goedert, M.; Scheres, S.H.W. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 2017, 547, 185–190. [Google Scholar] [CrossRef]
- Seidler, P.M.; Boyer, D.R.; Rodriguez, J.A.; Sawaya, M.R.; Cascio, D.; Murray, K.; Gonen, T.; Eisenberg, D.S. Structure-based inhibitors of tau aggregation. Nat. Chem. 2018, 10, 170–176. [Google Scholar] [CrossRef]
- Plumley, J.A.; Dannenberg, J.J. Comparison of beta-sheets of capped polyalanine with those of the tau-amyloid structures VQIVYK and VQIINK. A density functional theory study. J. Phys. Chem. B 2011, 115, 10560–10566. [Google Scholar] [CrossRef]
- Crowther, R.A.; Olesen, O.F.; Jakes, R.; Goedert, M. The microtubule binding repeats of tau protein assemble into filaments like those found in Alzheimer’s disease. FEBS Lett. 1992, 309, 199–202. [Google Scholar] [CrossRef]
- Bhopatkar, A.A.; Kayed, R. Flanking regions, amyloid cores, and polymorphism: The potential interplay underlying structural diversity. J. Biol. Chem. 2023, 299, 105122. [Google Scholar] [CrossRef]
- Falcon, B.; Zhang, W.; Murzin, A.G.; Murshudov, G.; Garringer, H.J.; Vidal, R.; Crowther, R.A.; Ghetti, B.; Scheres, S.H.W.; Goedert, M. Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature 2018, 561, 137–140. [Google Scholar] [CrossRef]
- Goedert, M. Cryo-EM structures of tau filaments from human brain. Essays Biochem. 2021, 65, 949–959. [Google Scholar] [CrossRef]
- Zhang, W.; Tarutani, A.; Newell, K.L.; Murzin, A.G.; Matsubara, T.; Falcon, B.; Vidal, R.; Garringer, H.J.; Shi, Y.; Ikeuchi, T.; et al. Novel tau filament fold in corticobasal degeneration. Nature 2020, 580, 283–287. [Google Scholar] [CrossRef]
- LoPresti, P.; Szuchet, S.; Papasozomenos, S.C.; Zinkowski, R.P.; Binder, L.I. Functional implications for the microtubule-associated protein tau: Localization in oligodendrocytes. Proc. Natl. Acad. Sci. USA 1995, 92, 10369–10373. [Google Scholar] [CrossRef]
- LoPresti, P. Regulation and differential expression of tau mRNA isoforms as oligodendrocytes mature in vivo: Implications for myelination. Glia 2002, 37, 250–257. [Google Scholar] [CrossRef]
- Klein, C.; Kramer, E.M.; Cardine, A.M.; Schraven, B.; Brandt, R.; Trotter, J. Process outgrowth of oligodendrocytes is promoted by interaction of fyn kinase with the cytoskeletal protein tau. J. Neurosci. 2002, 22, 698–707. [Google Scholar] [CrossRef]
- Seiberlich, V.; Bauer, N.G.; Schwarz, L.; Ffrench-Constant, C.; Goldbaum, O.; Richter-Landsberg, C. Downregulation of the microtubule associated protein tau impairs process outgrowth and myelin basic protein mRNA transport in oligodendrocytes. Glia 2015, 63, 1621–1635. [Google Scholar] [CrossRef]
- Richter-Landsberg, C. Protein aggregate formation in oligodendrocytes: Tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration. Biol. Chem. 2016, 397, 185–194. [Google Scholar] [CrossRef]
- Kahlson, M.A.; Colodner, K.J. Glial Tau Pathology in Tauopathies: Functional Consequences. J. Exp. Neurosci. 2015, 9, 43–50. [Google Scholar] [CrossRef]
- Komori, T. Tau-positive glial inclusions in progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Brain Pathol. 1999, 9, 663–679. [Google Scholar] [CrossRef] [PubMed]
- Rippon, G.A.; Staugaitis, S.M.; Chin, S.S.; Goldman, J.E.; Marder, K. Corticobasal syndrome with novel argyrophilic glial inclusions. Mov. Disord. 2005, 20, 598–602. [Google Scholar] [CrossRef] [PubMed]
- Higuchi, M.; Zhang, B.; Forman, M.S.; Yoshiyama, Y.; Trojanowski, J.Q.; Lee, V.M. Axonal degeneration induced by targeted expression of mutant human tau in oligodendrocytes of transgenic mice that model glial tauopathies. J. Neurosci. 2005, 25, 9434–9443. [Google Scholar] [CrossRef] [PubMed]
- Forrest, S.L.; Lee, S.; Nassir, N.; Martinez-Valbuena, I.; Sackmann, V.; Li, J.; Ahmed, A.; Tartaglia, M.C.; Ittner, L.M.; Lang, A.E.; et al. Cell-specific MAPT gene expression is preserved in neuronal and glial tau cytopathologies in progressive supranuclear palsy. Acta Neuropathol. 2023, 146, 395–414. [Google Scholar] [CrossRef] [PubMed]
- Narasimhan, S.; Changolkar, L.; Riddle, D.M.; Kats, A.; Stieber, A.; Weitzman, S.A.; Zhang, B.; Li, Z.; Roberson, E.D.; Trojanowski, J.Q.; et al. Human tau pathology transmits glial tau aggregates in the absence of neuronal tau. J. Exp. Med. 2020, 217, e20190783. [Google Scholar] [CrossRef] [PubMed]
- Narasimhan, S.; Guo, J.L.; Changolkar, L.; Stieber, A.; McBride, J.D.; Silva, L.V.; He, Z.; Zhang, B.; Gathagan, R.J.; Trojanowski, J.Q.; et al. Pathological Tau Strains from Human Brains Recapitulate the Diversity of Tauopathies in Nontransgenic Mouse Brain. J. Neurosci. 2017, 37, 11406–11423. [Google Scholar] [CrossRef]
- He, Z.; McBride, J.D.; Xu, H.; Changolkar, L.; Kim, S.J.; Zhang, B.; Narasimhan, S.; Gibbons, G.S.; Guo, J.L.; Kozak, M.; et al. Transmission of tauopathy strains is independent of their isoform composition. Nat. Commun. 2020, 11, 7. [Google Scholar] [CrossRef] [PubMed]
- Boluda, S.; Iba, M.; Zhang, B.; Raible, K.M.; Lee, V.M.; Trojanowski, J.Q. 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, 221–237. [Google Scholar] [CrossRef] [PubMed]
- Zareba-Paslawska, J.; Patra, K.; Kluzer, L.; Revesz, T.; Svenningsson, P. Tau Isoform-Driven CBD Pathology Transmission in Oligodendrocytes in Humanized Tau Mice. Front. Neurol. 2020, 11, 589471. [Google Scholar] [CrossRef]
- Ferrer, I.; Aguilo Garcia, M.; Carmona, M.; Andres-Benito, P.; Torrejon-Escribano, B.; Garcia-Esparcia, P.; Del Rio, J.A. Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies. Front. Aging Neurosci. 2019, 11, 112. [Google Scholar] [CrossRef]
- Yeung, M.S.; Zdunek, S.; Bergmann, O.; Bernard, S.; Salehpour, M.; Alkass, K.; Perl, S.; Tisdale, J.; Possnert, G.; Brundin, L.; et al. Dynamics of oligodendrocyte generation and myelination in the human brain. Cell 2014, 159, 766–774. [Google Scholar] [CrossRef]
- Ferrer, I. Oligodendrogliopathy in neurodegenerative diseases with abnormal protein aggregates: The forgotten partner. Prog. Neurobiol. 2018, 169, 24–54. [Google Scholar] [CrossRef] [PubMed]
- Gotz, J.; Chen, F.; Barmettler, R.; Nitsch, R.M. Tau filament formation in transgenic mice expressing P301L tau. J. Biol. Chem. 2001, 276, 529–534. [Google Scholar] [CrossRef] [PubMed]
- Gotz, J.; Tolnay, M.; Barmettler, R.; Chen, F.; Probst, A.; Nitsch, R.M. Oligodendroglial tau filament formation in transgenic mice expressing G272V tau. Eur. J. Neurosci. 2001, 13, 2131–2140. [Google Scholar] [CrossRef]
- Ren, Y.; Lin, W.L.; Sanchez, L.; Ceballos, C.; Polydoro, M.; Spires-Jones, T.L.; Hyman, B.T.; Dickson, D.W.; Sahara, N. Endogenous tau aggregates in oligodendrocytes of rTg4510 mice induced by human P301L tau. J. Alzheimer’s Dis. 2014, 38, 589–600. [Google Scholar] [CrossRef]
- Sahara, N.; Perez, P.D.; Lin, W.L.; Dickson, D.W.; Ren, Y.; Zeng, H.; Lewis, J.; Febo, M. Age-related decline in white matter integrity in a mouse model of tauopathy: An in vivo diffusion tensor magnetic resonance imaging study. Neurobiol. Aging 2014, 35, 1364–1374. [Google Scholar] [CrossRef] [PubMed]
- Viney, T.J.; Sarkany, B.; Ozdemir, A.T.; Hartwich, K.; Schweimer, J.; Bannerman, D.; Somogyi, P. Spread of pathological human Tau from neurons to oligodendrocytes and loss of high-firing pyramidal neurons in aging mice. Cell Rep. 2022, 41, 111646. [Google Scholar] [CrossRef] [PubMed]
- Ludvigson, A.E.; Luebke, J.I.; Lewis, J.; Peters, A. Structural abnormalities in the cortex of the rTg4510 mouse model of tauopathy: A light and electron microscopy study. Brain Struct. Funct. 2011, 216, 31–42. [Google Scholar] [CrossRef]
- Desai, M.K.; Sudol, K.L.; Janelsins, M.C.; Mastrangelo, M.A.; Frazer, M.E.; Bowers, W.J. Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia 2009, 57, 54–65. [Google Scholar] [CrossRef] [PubMed]
- Vanzulli, I.; Papanikolaou, M.; De-La-Rocha, I.C.; Pieropan, F.; Rivera, A.D.; Gomez-Nicola, D.; Verkhratsky, A.; Rodriguez, J.J.; Butt, A.M. Disruption of oligodendrocyte progenitor cells is an early sign of pathology in the triple transgenic mouse model of Alzheimer’s disease. Neurobiol. Aging 2020, 94, 130–139. [Google Scholar] [CrossRef]
- Tosto, G.; Zimmerman, M.E.; Carmichael, O.T.; Brickman, A.M.; Alzheimer’s Disease Neuroimaging Initiative. Predicting aggressive decline in mild cognitive impairment: The importance of white matter hyperintensities. JAMA Neurol. 2014, 71, 872–877. [Google Scholar] [CrossRef] [PubMed]
- Tosto, G.; Zimmerman, M.E.; Hamilton, J.L.; Carmichael, O.T.; Brickman, A.M.; Alzheimer’s Disease Neuroimaging Initiative. The effect of white matter hyperintensities on neurodegeneration in mild cognitive impairment. Alzheimer’s Dement. 2015, 11, 1510–1519. [Google Scholar] [CrossRef] [PubMed]
- Ramirez, J.; McNeely, A.A.; Scott, C.J.M.; Masellis, M.; Black, S.E.; Alzheimer’s Disease Neuroimaging Initiative. White matter hyperintensity burden in elderly cohort studies: The Sunnybrook Dementia Study, Alzheimer’s Disease Neuroimaging Initiative, and Three-City Study. Alzheimer’s Dement. 2016, 12, 203–210. [Google Scholar] [CrossRef] [PubMed]
- Behrendt, G.; Baer, K.; Buffo, A.; Curtis, M.A.; Faull, R.L.; Rees, M.I.; Gotz, M.; Dimou, L. Dynamic changes in myelin aberrations and oligodendrocyte generation in chronic amyloidosis in mice and men. Glia 2013, 61, 273–286. [Google Scholar] [CrossRef] [PubMed]
- Gagyi, E.; Kormos, B.; Castellanos, K.J.; Valyi-Nagy, K.; Korneff, D.; LoPresti, P.; Woltjer, R.; Valyi-Nagy, T. Decreased oligodendrocyte nuclear diameter in Alzheimer’s disease and Lewy body dementia. Brain Pathol. 2012, 22, 803–810. [Google Scholar] [CrossRef] [PubMed]
- Sadick, J.S.; O’Dea, M.R.; Hasel, P.; Dykstra, T.; Faustin, A.; Liddelow, S.A. Astrocytes and oligodendrocytes undergo subtype-specific transcriptional changes in Alzheimer’s disease. Neuron 2022, 110, 1788–1805.e1710. [Google Scholar] [CrossRef] [PubMed]
- Grubman, A.; Chew, G.; Ouyang, J.F.; Sun, G.; Choo, X.Y.; McLean, C.; Simmons, R.K.; Buckberry, S.; Vargas-Landin, D.B.; Poppe, D.; et al. A single-cell atlas of entorhinal cortex from individuals with Alzheimer’s disease reveals cell-type-specific gene expression regulation. Nat. Neurosci. 2019, 22, 2087–2097. [Google Scholar] [CrossRef] [PubMed]
- Mathys, H.; Davila-Velderrain, J.; Peng, Z.; Gao, F.; Mohammadi, S.; Young, J.Z.; Menon, M.; He, L.; Abdurrob, F.; Jiang, X.; et al. Single-cell transcriptomic analysis of Alzheimer’s disease. Nature 2019, 570, 332–337. [Google Scholar] [CrossRef] [PubMed]
- Jiskoot, L.C.; Bocchetta, M.; Nicholas, J.M.; Cash, D.M.; Thomas, D.; Modat, M.; Ourselin, S.; Rombouts, S.; Dopper, E.G.P.; Meeter, L.H.; et al. Presymptomatic white matter integrity loss in familial frontotemporal dementia in the GENFI cohort: A cross-sectional diffusion tensor imaging study. Ann. Clin. Transl. Neurol. 2018, 5, 1025–1036. [Google Scholar] [CrossRef]
- Feis, R.A.; Bouts, M.; Panman, J.L.; Jiskoot, L.C.; Dopper, E.G.P.; Schouten, T.M.; de Vos, F.; van der Grond, J.; van Swieten, J.C.; Rombouts, S. Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI. Neuroimage Clin. 2019, 22, 101718. [Google Scholar] [CrossRef]
- Chao, L.L.; Schuff, N.; Clevenger, E.M.; Mueller, S.G.; Rosen, H.J.; Gorno-Tempini, M.L.; Kramer, J.H.; Miller, B.L.; Weiner, M.W. Patterns of white matter atrophy in frontotemporal lobar degeneration. Arch. Neurol. 2007, 64, 1619–1624. [Google Scholar] [CrossRef] [PubMed]
- Borroni, B.; Brambati, S.M.; Agosti, C.; Gipponi, S.; Bellelli, G.; Gasparotti, R.; Garibotto, V.; Di Luca, M.; Scifo, P.; Perani, D.; et al. Evidence of white matter changes on diffusion tensor imaging in frontotemporal dementia. Arch. Neurol. 2007, 64, 246–251. [Google Scholar] [CrossRef] [PubMed]
- Agosta, F.; Galantucci, S.; Svetel, M.; Lukic, M.J.; Copetti, M.; Davidovic, K.; Tomic, A.; Spinelli, E.G.; Kostic, V.S.; Filippi, M. Clinical, cognitive, and behavioural correlates of white matter damage in progressive supranuclear palsy. J. Neurol. 2014, 261, 913–924. [Google Scholar] [CrossRef] [PubMed]
- Ling, H.; Kovacs, G.G.; Vonsattel, J.P.; Davey, K.; Mok, K.Y.; Hardy, J.; Morris, H.R.; Warner, T.T.; Holton, J.L.; Revesz, T. Astrogliopathy predominates the earliest stage of corticobasal degeneration pathology. Brain 2016, 139, 3237–3252. [Google Scholar] [CrossRef] [PubMed]
- Boxer, A.L.; Geschwind, M.D.; Belfor, N.; Gorno-Tempini, M.L.; Schauer, G.F.; Miller, B.L.; Weiner, M.W.; Rosen, H.J. Patterns of brain atrophy that differentiate corticobasal degeneration syndrome from progressive supranuclear palsy. Arch. Neurol. 2006, 63, 81–86. [Google Scholar] [CrossRef] [PubMed]
- Rosler, T.W.; Tayaranian Marvian, A.; Brendel, M.; Nykanen, N.P.; Hollerhage, M.; Schwarz, S.C.; Hopfner, F.; Koeglsperger, T.; Respondek, G.; Schweyer, K.; et al. Four-repeat tauopathies. Prog. Neurobiol. 2019, 180, 101644. [Google Scholar] [CrossRef] [PubMed]
- Yoshida, M. [Neuropathology of tauopathy]. Brain Nerve 2013, 65, 1445–1458. [Google Scholar] [PubMed]
- Waheed, Z.; Choudhary, J.; Jatala, F.H.; Fatimah; Noor, A.; Zerr, I.; Zafar, S. The Role of Tau Proteoforms in Health and Disease. Mol. Neurobiol. 2023, 60, 5155–5166. [Google Scholar] [CrossRef] [PubMed]
- Dutta, D.; Jana, M.; Paidi, R.K.; Majumder, M.; Raha, S.; Dasarathy, S.; Pahan, K. Tau fibrils induce glial inflammation and neuropathology via TLR2 in Alzheimer’s disease-related mouse models. J. Clin. Investig. 2023, 133, e161987. [Google Scholar] [CrossRef]
- Eltom, K.; Mothes, T.; Libard, S.; Ingelsson, M.; Erlandsson, A. Astrocytic accumulation of tau fibrils isolated from Alzheimer’s disease brains induces inflammation, cell-to-cell propagation and neuronal impairment. Acta Neuropathol. Commun. 2024, 12, 34. [Google Scholar] [CrossRef]
- Gratuze, M.; Chen, Y.; Parhizkar, S.; Jain, N.; Strickland, M.R.; Serrano, J.R.; Colonna, M.; Ulrich, J.D.; Holtzman, D.M. Activated microglia mitigate Abeta-associated tau seeding and spreading. J. Exp. Med. 2021, 218, e20210542. [Google Scholar] [CrossRef]
- Leyns, C.E.G.; Gratuze, M.; Narasimhan, S.; Jain, N.; Koscal, L.J.; Jiang, H.; Manis, M.; Colonna, M.; Lee, V.M.Y.; Ulrich, J.D.; et al. TREM2 function impedes tau seeding in neuritic plaques. Nat. Neurosci. 2019, 22, 1217–1222. [Google Scholar] [CrossRef]
- Martini-Stoica, H.; Cole, A.L.; Swartzlander, D.B.; Chen, F.; Wan, Y.W.; Bajaj, L.; Bader, D.A.; Lee, V.M.Y.; Trojanowski, J.Q.; Liu, Z.; et al. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 2018, 215, 2355–2377. [Google Scholar] [CrossRef]
Post-Translational Modifications | Target Amino Acid Residues | Enzymes Involved | Functional Impact | References |
---|---|---|---|---|
Phosphorylation | 1. Thr-Pro and Ser-Pro motifs (85 known until now). 2. Tyr residues (5 identified until now). | Microtubule affinity-regulating kinases (MARKs), cAMP-dependent protein kinase (PKA), Ca2+- or calmodulin-dependent protein kinase II (CaMKII), glycogen synthase kinase-3β (GSK-3β), SRC family protein kinases (LCK, SYK and FYN), ABL family protein kinases (ARG and ABL1). | 1. Phosphorylation in repeat domains and flanking regions (Ser262, Thr231, etc.) reduces its affinity to microtubules. 2. Phosphorylation at Ser202-Thr205 enhances its self-aggregation and NFT formation, whereas impairs axonal transport. 3. Phosphorylation decreases Tau–FYN interaction and impairs sorting of myelin proteins and neuron–glia interactions. 4. Phosphorylation reduces tau cleavage by other proteases (caspases). | [5,32,41,42,43,44,45,46,47] |
Acetylation | Lys residues in the repeat domains and flanking regions of tau. More than 20 Lys residues in the full-length tau were found to be acetylated. | Acetylation by P300 acetyltransferase or by CREB-binding protein and deacetylation by sirtuin 1 (SIRT1) and histone deacetylase 6 (HDAC6). | 1. Acetylation at Lys163, Lys280, Lys281, or Lys369 prevents its degradation. Acetylation at Lys274 and Lys281 reduces its binding to microtubules. Lys274 acetylation is found in NFTs of AD brain and correlates with disease pathology. 2. Acetylation at Lys259, Lys290, Lys321, or Lys353 promotes its degradation and reduces phosphorylation. 3. Acetylation at certain Lys residues blocks ubiquitination and promotes formation of more tau oligomers and aggregates resulting in synaptic degeneration and cognitive deficits. | [48,49,50,51,52,53,54] |
Nitration | The Tyr amino acids present in the structure of tau have been shown to be nitrated (addition of -NO2). Some of these nitrations (Tyr197) happen in healthy brains, whereas some nitrations (Tyr18, Tyr29, Tyr394) are found in AD brains. | Nitration of tau, like other proteins associated with neurodegeneration, is mainly caused by reactive nitrogen species such as peroxynitrite formed because of nitrosative stress. | Nitrated tau was shown to have reduced binding with microtubule in vitro. Nitrated tau has been found in NFT-bearing neurons and in glial tau inclusions. | [55,56,57,58,59] |
Ubiquitination | A total of 17 Lys residues in the 2N4R form of tau are known to be ubiquitinated and majority of these Lys residues are buried in the microtubule-binding domain. | Multiple E3 ubiquitin ligases such as C-terminus of the Hsc70-interacting protein (CHIP), the TNF receptor-associated factor 6 (TRAF6), and axotrophin/MARCH7 have been reported to ubiquitinate tau through Lys 48- and Lys 63-dependent mechanisms. | 1. Mono- and poly-ubiquitination of tau at distinct Lys residues drive its proteasomal degradation in cells. 2. Phosphorylation of tau may precede ubiquitination and promotes or inhibits ubiquitin-mediated degradation of insoluble tau depending on the site of Lys residue in the tau protein. Therefore, ubiquitinated tau is also found in the pathological tau inclusions and NFTs in tauopathy brain. 3. Soluble tau is shown to be ubiquitinated through Lys 63 modification that leads to autophagy-mediated clearance of tau. 4. In addition, chronic impairments of the ubiquitin–proteasome system further upregulates tau inclusion formation and pathology. | [60,61,62,63,64] |
Sumoylation | Small ubiquitin-like modifiers (SUMOs) are bound to Lys residues of tau inhibiting ubiquitin binding and proteolysis of tau. | Sumoylation is carried out by E1 activating enzyme, E2 conjugating enzyme, and E3 ligase of the ubiquitination machinery. | 1. Sumoylation at Lys340, present in the microtubule-binding domain, promotes hyperphosphorylation of tau and inhibits ubiquitin-mediated degradation, leading to enhanced aggregation of tau. 2. Sumoylation also hinders tau clearance by the autophagy-lysosome pathway, as shown in the rTg4510 mice model of tauopathy. | [57,65,66,67] |
O-GlcNAcylation (O-GlcNAc) | Ser-Thr hydroxyl groups that are prone to be phosphorylated are also O-glucosylated by N-acetylglucosamine. | O-GlcNAc transferase (OGT) transfers the addition of N-acetylglucosamine to serine or threonine hydroxyl groups of tau protein. O-GlcNAcase (OGA) removes the N-acetylglucosamine group from tau. OGT is transcriptionally upregulated by CREB binding to its promoter (CRE site). In contrast, SIRT1-mediated deacetylation of CREB reduces OGT transcription and inhibits O-GlcNAc of tau. | 1. O-GlcNAc inhibits phosphorylation and pathological aggregation of tau. Higher O-GlcNAc of tau has been shown to protect brain from tau-induced impairments. 2. O-GlcNAc of tau is decreased in AD and perhaps caused by reduced glucose uptake and metabolism in AD brains. | [68,69,70,71] |
Truncation | Around 60 cleavage sites have been identified in full-length tau and several of these truncated forms are found in AD brains. | Disintegrin and metallopeptidase domain 10, asparagine endopeptidase (AEP), calpains, caspases, cathepsins, chymotrypsin. In addition, autoproteolysis of tau occurs at K281-L282 and K340-S341 when acetylation happens on Lys residues. | 1. The cleavage of tau may expose the microtubule-binding domains and facilitate its self-aggregation. Truncated tau fragments including E391- or D421-truncated Tau, Tau304–380 fragment, K18/K280, and K12 aggregate without the presence of negatively charged inducers. 2. Cleaved Tau N368 fragments are more abundant in animal models of tauopathy while colocalizing with NFT. 3. Deletion of the first 150–230 amino acids of tau results in more phosphorylation and aggregation. Similarly, deletion of the last 50 amino acids of tau causes enhanced phosphorylation and self-aggregation. | [72,73,74,75,76,77,78,79,80] |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Majumder, M.; Dutta, D. Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration. Cells 2024, 13, 1112. https://doi.org/10.3390/cells13131112
Majumder M, Dutta D. Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration. Cells. 2024; 13(13):1112. https://doi.org/10.3390/cells13131112
Chicago/Turabian StyleMajumder, Moumita, and Debashis Dutta. 2024. "Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration" Cells 13, no. 13: 1112. https://doi.org/10.3390/cells13131112
APA StyleMajumder, M., & Dutta, D. (2024). Oligodendrocyte Dysfunction in Tauopathy: A Less Explored Area in Tau-Mediated Neurodegeneration. Cells, 13(13), 1112. https://doi.org/10.3390/cells13131112