Tau Abnormalities and Autophagic Defects in Neurodegenerative Disorders; A Feed-forward Cycle

Authors

  • Nastaran Samimi 1. Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran 
 2. Department of Brain and Cognitive Sciences, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
  • Akiko Asada 3. Department of Biological Sciences, School of Science, Tokyo Metropolitan University, Tokyo, Japan 
 4. Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan
  • Kanae Ando 3. Department of Biological Sciences, School of Science, Tokyo Metropolitan University, Tokyo, Japan 
 4. Graduate School of Science, Tokyo Metropolitan University, Tokyo, Japan

DOI:

https://doi.org/10.31661/gmj.v9i.1681

Keywords:

Neurodegenerative Diseases, Tauopathy, Autophagy, Microtubule Binding Protein, Tau, Phosphorylation, Vesicle Trafficking

Abstract

Abnormal deposition of misfolded proteins is a neuropathological characteristic shared by many neurodegenerative disorders including Alzheimer’s disease (AD). Generation of excessive amounts of aggregated proteins and impairment of degradation systems for misfolded proteins such as autophagy can lead to accumulation of proteins in diseased neurons. Molecules that contribute to both these effects are emerging as critical players in disease pathogenesis. Furthermore, impairment of autophagy under disease conditions can be both a cause and a consequence of abnormal protein accumulation. Specifically, disease-causing proteins can impair autophagy, which further enhances the accumulation of abnormal proteins. In this short review, we focus on the relationship between the microtubule-associated protein tau and autophagy to highlight a feed-forward mechanism in disease pathogenesis. [GMJ.2020;9:e1681]

References

Klaips CL, Jayaraj GG, Hartl FU. Pathways of cellular proteostasis in aging and disease. J Cell Biol. 2018;217(1):51-63. https://doi.org/10.1083/jcb.201709072PMid:29127110 PMCid:PMC5748993 Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer's disease and related disorders. Nat Rev Neurosci. 2007;8(9):663-72. https://doi.org/10.1038/nrn2194PMid:17684513 Stoothoff WH, Johnson GV. Tau phosphorylation: physiological and pathological consequences. Biochim Biophys Acta. 2005;1739(2-3):280-97. https://doi.org/10.1016/j.bbadis.2004.06.017PMid:15615646 Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17(1):5-21. https://doi.org/10.1038/nrn.2015.1PMid:26631930 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(13):4913-7. https://doi.org/10.1073/pnas.83.13.4913PMid:3088567 PMCid:PMC323854 Hasegawa M, Morishima-Kawashima M, Takio K, Suzuki M, Titani K, Ihara Y. Protein sequence and mass spectrometric analyses of tau in the Alzheimer's disease brain. J Biol Chem. 1992;267(24):17047-54. Hanger DP, Betts JC, Loviny TL, Blackstock WP, Anderton BH. New phosphorylation sites identified in hyperphosphorylated tau (paired helical filament-tau) from Alzheimer's disease brain using nanoelectrospray mass spectrometry. J Neurochem. 1998;71(6):2465-76. https://doi.org/10.1046/j.1471-4159.1998.71062465.xPMid:9832145 Morishima-Kawashima M, Hasegawa M, Takio K, Suzuki M, Yoshida H, Titani K et al. Proline-directed and non-proline-directed phosphorylation of PHF-tau. J Biol Chem. 1995;270(2):823-9. https://doi.org/10.1074/jbc.270.2.823PMid:7822317 Holtzman DM, Carrillo MC, Hendrix JA, Bain LJ, Catafau AM, Gault LM et al. Tau: From research to clinical development. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2016;12(10):1033-9. https://doi.org/10.1016/j.jalz.2016.03.018PMid:27154059 Wolfe MS. Tau mutations in neurodegenerative diseases. J Biol Chem. 2009;284(10):6021-5. https://doi.org/10.1074/jbc.R800013200PMid:18948254 Goedert M, Spillantini MG. A century of Alzheimer's disease. Science. 2006;314(5800):777-81. https://doi.org/10.1126/science.1132814PMid:17082447 Wang JZ, Xia YY, Grundke-Iqbal I, Iqbal K. Abnormal hyperphosphorylation of tau: sites, regulation, and molecular mechanism of neurofibrillary degeneration. J Alzheimers Dis. 2013;33 Suppl 1:S123-39. https://doi.org/10.3233/JAD-2012-129031PMid:22710920 Johnson GV, Stoothoff WH. Tau phosphorylation in neuronal cell function and dysfunction. J Cell Sci. 2004;117(Pt 24):5721-9. https://doi.org/10.1242/jcs.01558PMid:15537830 Kimura T, Ishiguro K, Hisanaga S. Physiological and pathological phosphorylation of tau by Cdk5. Front Mol Neurosci. 2014;7:65. https://doi.org/10.3389/fnmol.2014.00065PMid:25076872 PMCid:PMC4097945 Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer's disease. J Alzheimer's dis. 2006;9(3 Suppl):309-17. https://doi.org/10.3233/JAD-2006-9S335PMid:16914869 Leugers CJ, Koh JY, Hong W, Lee G. Tau in MAPK activation. Front Neurol. 2013;4:161. https://doi.org/10.3389/fneur.2013.00161PMid:24146661 PMCid:PMC3797993 Nishimura I, Yang Y, Lu B. PAR-1 kinase plays an initiator role in a temporally ordered phosphorylation process that confers tau toxicity in Drosophila. Cell. 2004;116(5):671-82. https://doi.org/10.1016/S0092-8674(04)00170-9 Drewes G, Ebneth A, Preuss U, Mandelkow EM, Mandelkow E. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell. 1997;89(2):297-308. https://doi.org/10.1016/S0092-8674(00)80208-1 Mairet-Coello G, Courchet J, Pieraut S, Courchet V, Maximov A, Polleux F. The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Abeta oligomers through Tau phosphorylation. Neuron. 2013;78(1):94-108. https://doi.org/10.1016/j.neuron.2013.02.003PMid:23583109 PMCid:PMC3784324 Thornton C, Bright NJ, Sastre M, Muckett PJ, Carling D. AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid beta-peptide exposure. Biochem J. 2011;434(3):503-12. https://doi.org/10.1042/BJ20101485PMid:21204788 Iijima-Ando K, Zhao L, Gatt A, Shenton C, Iijima K. A DNA damage-activated checkpoint kinase phosphorylates tau and enhances tau-induced neurodegeneration. Hum Mol Genet. 2010;19(10):1930-8. https://doi.org/10.1093/hmg/ddq068PMid:20159774 PMCid:PMC2860892 Sironi JJ, Yen SH, Gondal JA, Wu Q, Grundke-Iqbal I, Iqbal K. Ser-262 in human recombinant tau protein is a markedly more favorable site for phosphorylation by CaMKII than PKA or PhK. FEBS Lett. 1998;436(3):471-5. https://doi.org/10.1016/S0014-5793(98)01185-5 Pei JJ, An WL, Zhou XW, Nishimura T, Norberg J, Benedikz E et al. P70 S6 kinase mediates tau phosphorylation and synthesis. FEBS Lett. 2006;580(1):107-14. https://doi.org/10.1016/j.febslet.2005.11.059PMid:16364302 Lasagna-Reeves CA, de Haro M, Hao S, Park J, Rousseaux MW, Al-Ramahi I et al. Reduction of Nuak1 Decreases Tau and Reverses Phenotypes in a Tauopathy Mouse Model. Neuron. 2016;92(2):407-18. https://doi.org/10.1016/j.neuron.2016.09.022PMid:27720485 PMCid:PMC5745060 Saito T, Oba T, Shimizu S, Asada A, Iijima KM, Ando K. Cdk5 increases MARK4 activity and augments pathological tau accumulation and toxicity through tau phosphorylation at Ser262. Hum Mol Genet. 2019. https://doi.org/10.1093/hmg/ddz120PMid:31174206 Ohsumi Y. Historical landmarks of autophagy research. Cell Res. 2014;24(1):9-23. https://doi.org/10.1038/cr.2013.169PMid:24366340 PMCid:PMC3879711 Uddin MS, Stachowiak A, Mamun AA, Tzvetkov NT, Takeda S, Atanasov AG et al. Autophagy and Alzheimer's Disease: From Molecular Mechanisms to Therapeutic Implications. Front Aging Neurosci. 2018;10:04. https://doi.org/10.3389/fnagi.2018.00004PMid:29441009 PMCid:PMC5797541 Tekirdag K, Cuervo AM. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J Biol Chem. 2018;293(15):5414-24. https://doi.org/10.1074/jbc.R117.818237PMid:29247007 PMCid:PMC5900761 Ravikumar B, Acevedo-Arozena A, Imarisio S, Berger Z, Vacher C, O'Kane CJ et al. Dynein mutations impair autophagic clearance of aggregate-prone proteins. Nature genetics. 2005;37(7):771. https://doi.org/10.1038/ng1591PMid:15980862 Menzies FM, Fleming A, Rubinsztein DC. Compromised autophagy and neurodegenerative diseases. Nat Rev Neurosci. 2015;16(6):345-57. https://doi.org/10.1038/nrn3961PMid:25991442 Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol. 2011;12(1):21-35. https://doi.org/10.1038/nrm3025PMid:21157483 PMCid:PMC3390257 Caccamo A, Branca C, Talboom JS, Shaw DM, Turner D, Ma L et al. Reducing Ribosomal Protein S6 Kinase 1 Expression Improves Spatial Memory and Synaptic Plasticity in a Mouse Model of Alzheimer's Disease. J Neurosci. 2015;35(41):14042-56. https://doi.org/10.1523/JNEUROSCI.2781-15.2015PMid:26468204 PMCid:PMC4604237 Oddo S. The role of mTOR signaling in Alzheimer disease. Front Biosci (Schol Ed). 2012;4:941-52. https://doi.org/10.2741/s310PMid:22202101 Lee MJ, Lee JH, Rubinsztein DC. Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system. Prog Neurobiol. 2013;105:49-59. https://doi.org/10.1016/j.pneurobio.2013.03.001PMid:23528736 Criollo A, Maiuri MC, Tasdemir E, Vitale I, Fiebig AA, Andrews D et al. Regulation of autophagy by the inositol trisphosphate receptor. Cell Death Differ. 2007;14(5):1029-39. https://doi.org/10.1038/sj.cdd.4402099PMid:17256008 Dickey CA, Kamal A, Lundgren K, Klosak N, Bailey RM, Dunmore J et al. The high-affinity HSP90-CHIP complex recognizes and selectively degrades phosphorylated tau client proteins. J Clin Invest. 2007;117(3):648-58. https://doi.org/10.1172/JCI29715PMid:17304350 PMCid:PMC1794119 Dickey CA, Dunmore J, Lu B, Wang JW, Lee WC, Kamal A et al. HSP induction mediates selective clearance of tau phosphorylated at proline-directed Ser/Thr sites but not KXGS (MARK) sites. FASEB J. 2006;20(6):753-5. https://doi.org/10.1096/fj.05-5343fjePMid:16464956 Chiku T, Hayashishita M, Saito T, Oka M, Shinno K, Ohtake Y et al. S6K/p70S6K1 protects against tau-mediated neurodegeneration by decreasing the level of tau phosphorylated at Ser262 in a Drosophila model of tauopathy. Neurobiol Aging. 2018;71:255-64. https://doi.org/10.1016/j.neurobiolaging.2018.07.021PMid:30172839 Dolan PJ, Johnson GV. A caspase cleaved form of tau is preferentially degraded through the autophagy pathway. J Biol Chem. 2010;285(29):21978-87. https://doi.org/10.1074/jbc.M110.110940PMid:20466727 PMCid:PMC2903354 Schaeffer V, Lavenir I, Ozcelik S, Tolnay M, Winkler DT, Goedert M. Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy. Brain. 2012;135(Pt 7):2169-77. https://doi.org/10.1093/brain/aws143PMid:22689910 PMCid:PMC3381726 Jo C, Gundemir S, Pritchard S, Jin YN, Rahman I, Johnson GV. Nrf2 reduces levels of phosphorylated tau protein by inducing autophagy adaptor protein NDP52. Nat Commun. 2014;5:3496. https://doi.org/10.1038/ncomms4496PMid:24667209 PMCid:PMC3990284 Ciechanover A, Kwon YT. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Exp Mol Med. 2015;47:e147. https://doi.org/10.1038/emm.2014.117PMid:25766616 PMCid:PMC4351408 Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, Isidoro C et al. Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression. Eur J Neurosci. 2008;27(5):1119-30. https://doi.org/10.1111/j.1460-9568.2008.06084.xPMid:18294209 Wang Y, Martinez-Vicente M, Kruger U, Kaushik S, Wong E, Mandelkow EM et al. Synergy and antagonism of macroautophagy and chaperone-mediated autophagy in a cell model of pathological tau aggregation. Autophagy. 2010;6(1):182-3. https://doi.org/10.4161/auto.6.1.10815PMid:20023429 Wang JZ, Grundke-Iqbal I, Iqbal K. Kinases and phosphatases and tau sites involved in Alzheimer neurofibrillary degeneration. Eur J Neurosci. 2007;25(1):59-68. https://doi.org/10.1111/j.1460-9568.2006.05226.xPMid:17241267 PMCid:PMC3191918 Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer's disease and other tauopathies. Aging Cell. 2013;12(3):370-80. https://doi.org/10.1111/acel.12057PMid:23425014 PMCid:PMC3655115 Guo F, Liu X, Cai H, Le W. Autophagy in neurodegenerative diseases: pathogenesis and therapy. Brain Pathol. 2018;28(1):3-13. https://doi.org/10.1111/bpa.12545PMid:28703923 PMCid:PMC5739982 Ando K, Oka M, Ohtake Y, Hayashishita M, Shimizu S, Hisanaga S et al. Tau phosphorylation at Alzheimer's disease-related Ser356 contributes to tau stabilization when PAR-1/MARK activity is elevated. Biochem Biophys Res Commun. 2016;478(2):929-34. https://doi.org/10.1016/j.bbrc.2016.08.053PMid:27520376 PMCid:PMC5675734 Li L, Guan KL. Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a negative regulator of the mammalian target of rapamycin complex 1 (mTORC1). J Biol Chem. 2013;288(1):703-8. https://doi.org/10.1074/jbc.C112.396903PMid:23184942 PMCid:PMC3537069 Kimura T, Sharma G, Ishiguro K, Hisanaga SI. Phospho-Tau Bar Code: Analysis of Phosphoisotypes of Tau and Its Application to Tauopathy. Front Neurosci. 2018;12:44. https://doi.org/10.3389/fnins.2018.00044PMid:29467609 PMCid:PMC5808175 Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA. Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease. Brain Res. 1997;763(2):145-58. https://doi.org/10.1016/S0006-8993(97)00384-3 Ferreira A, Bigio EH. Calpain-mediated tau cleavage: a mechanism leading to neurodegeneration shared by multiple tauopathies. Mol Med. 2011;17(7-8):676-85. https://doi.org/10.2119/molmed.2010.00220PMid:21442128 PMCid:PMC3146621 Johnson CW, Melia TJ, Yamamoto A. Modulating macroautophagy: a neuronal perspective. Future Med Chem. 2012;4(13):1715-31. https://doi.org/10.4155/fmc.12.112PMid:22924509 PMCid:PMC3566761 Vijayan V, Verstreken P. Autophagy in the presynaptic compartment in health and disease. J Cell Biol. 2017;216(7):1895-906. https://doi.org/10.1083/jcb.201611113PMid:28515275 PMCid:PMC5496617 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(6):1051-63. https://doi.org/10.1083/jcb.200108057PMid:11901170 PMCid:PMC2173473 Ittner LM, Fath T, Ke YD, Bi M, van Eersel J, Li KM et al. Parkinsonism and impaired axonal transport in a mouse model of frontotemporal dementia. Proc Natl Acad Sci U S A. 2008;105(41):15997-6002. https://doi.org/10.1073/pnas.0808084105PMid:18832465 PMCid:PMC2572931 Rodriguez-Martin T, Pooler AM, Lau DHW, Morotz GM, De Vos KJ, Gilley J et al. Reduced number of axonal mitochondria and tau hypophosphorylation in mouse P301L tau knockin neurons. Neurobiol Dis. 2016;85:1-10. https://doi.org/10.1016/j.nbd.2015.10.007PMid:26459111 PMCid:PMC4684147 Chee FC, Mudher A, Cuttle MF, Newman TA, MacKay D, Lovestone S et al. Over-expression of tau results in defective synaptic transmission in Drosophila neuromuscular junctions. Neurobiol Dis. 2005;20(3):918-28. https://doi.org/10.1016/j.nbd.2005.05.029PMid:16023860 Kraemer BC, Zhang B, Leverenz JB, Thomas JH, Trojanowski JQ, Schellenberg GD. Neurodegeneration and defective neurotransmission in a Caenorhabditis elegans model of tauopathy. Proc Natl Acad Sci U S A. 2003;100(17):9980-5. https://doi.org/10.1073/pnas.1533448100PMid:12872001 PMCid:PMC187908 Maday S, Holzbaur EL. Compartment-Specific Regulation of Autophagy in Primary Neurons. J Neurosci. 2016;36(22):5933-45. https://doi.org/10.1523/JNEUROSCI.4401-15.2016PMid:27251616 PMCid:PMC4887563 Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron. 2014;82(4):756-71. https://doi.org/10.1016/j.neuron.2014.05.004PMid:24853936 PMCid:PMC4135182 Decker JM, Kruger L, Sydow A, Zhao S, Frotscher M, Mandelkow E et al. Pro-aggregant Tau impairs mossy fiber plasticity due to structural changes and Ca(++) dysregulation. Acta Neuropathol Commun. 2015;3:23. https://doi.org/10.1186/s40478-015-0193-3PMid:25853683 PMCid:PMC4384391 Zhou L, McInnes J, Wierda K, Holt M, Herrmann AG, Jackson RJ et al. Tau association with synaptic vesicles causes presynaptic dysfunction. Nature communications. 2017;8:15295. https://doi.org/10.1038/ncomms15295PMid:28492240 PMCid:PMC5437271 McInnes J, Wierda K, Snellinx A, Bounti L, Wang YC, Stancu IC et al. Synaptogyrin-3 Mediates Presynaptic Dysfunction Induced by Tau. Neuron. 2018;97(4):823-35 e8. https://doi.org/10.1016/j.neuron.2018.01.022PMid:29398363 Ittner A, Ittner LM. Dendritic Tau in Alzheimer's Disease. Neuron. 2018;99(1):13-27. https://doi.org/10.1016/j.neuron.2018.06.003PMid:30001506 Akwa Y, Gondard E, Mann A, Capetillo-Zarate E, Alberdi E, Matute C et al. Synaptic activity protects against AD and FTD-like pathology via autophagic-lysosomal degradation. Mol Psychiatry. 2018;23(6):1530-40. https://doi.org/10.1038/mp.2017.142PMid:28696431 PMCid:PMC5641448 Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19(8):983-97. https://doi.org/10.1038/nm.3232PMid:23921753 Lee JH, Yu WH, Kumar A, Lee S, Mohan PS, Peterhoff CM et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell. 2010;141(7):1146-58. https://doi.org/10.1016/j.cell.2010.05.008PMid:20541250 PMCid:PMC3647462 Plotegher N, Civiero L. Neuronal autophagy, alpha-synuclein clearance, and LRRK2 regulation: a lost equilibrium in parkinsonian brain. J Neurosci. 2012;32(43):14851-3. https://doi.org/10.1523/JNEUROSCI.3588-12.2012PMid:23100407 PMCid:PMC6704826 Xia Q, Wang H, Hao Z, Fu C, Hu Q, Gao F et al. TDP-43 loss of function increases TFEB activity and blocks autophagosome-lysosome fusion. EMBO J. 2016;35(2):121-42. https://doi.org/10.15252/embj.201591998PMid:26702100 PMCid:PMC4718457 Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741-52. https://doi.org/10.1038/nrm2239 Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT. Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol. 2007;170(1):75-86. https://doi.org/10.2353/ajpath.2007.060524PMid:17200184 PMCid:PMC1762689 Toth ML, Simon P, Kovacs AL, Vellai T. Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans. J Cell Sci. 2007;120(Pt 6):1134-41. https://doi.org/10.1242/jcs.03401PMid:17327275 Chu CT, Zhu J, Dagda R. Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death. Autophagy. 2007;3(6):663-6. https://doi.org/10.4161/auto.4625PMid:17622797 PMCid:PMC2779565 Hirt J, Porter K, Dixon A, McKinnon S, Liton PB. Contribution of autophagy to ocular hypertension and neurodegeneration in the DBA/2J spontaneous glaucoma mouse model. Cell Death Discov. 2018;4:14. https://doi.org/10.1038/s41420-018-0077-yPMid:30210817 PMCid:PMC6127277

Published

2020-01-27

Issue

Section

Review Article