The Korean Journal of Physiology and Pharmacology

The Korean Society of Pharmacology (대한약리학회)
권호 표지
DOI QR코드

DOI QR Code

Suppression of Autophagy and Activation of Glycogen Synthase Kinase 3beta Facilitate the Aggregate Formation of Tau

  • Kim, Song-In (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Lee, Won-Ki (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Kang, Sang-Soo (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Lee, Sue-Young (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Jeong, Myeong-Ja (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Lee, Hee-Jae (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Kim, Sung-Soo (Department of Pharmacology, College of Medicine, Kangwon National University) ;
  • Johnson, Gall V.W. (Department of Anesthesiology, University of Rochester) ;
  • Chun, Wan-Joo (Department of Pharmacology, College of Medicine, Kangwon National University)
  • Received : 2011.03.25
  • Accepted : 2011.04.20
  • Published : 2011.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer's disease. GSK3β has been reported to play a major role in the NFT formation of tau. Dysfunction of autophagy might facilitate the aggregate formation of tau. The present study examined the role of GSK3${\beta}$-mediated phosphorylation of tau species on their autophagic degradation. We transfected wild type tau (T4), caspase-3-cleaved tau at Asp421 (T4C3), or pseudophosphorylated tau at Ser396/Ser404 (T4-2EC) in the presence of active or enzyme-inactive GSK3${\beta}$. Trehalose and 3-methyladenine (3-MA) were used to enhance or inhibit autophagic activity, respectively. All tau species showed increased accumulation with 3-MA treatment whereas reduced with trehalose, indicating that tau undergoes autophagic degradation. However, T4C3 and T4-2EC showed abundant formation of oligomers than T4. Active GSK3${\beta}$ in the presence of 3-MA resulted in significantly increased formation of insoluble tau aggregates. These results indicate that GSK3${\beta}$-mediated phosphorylation and compromised autophagic activity significantly contribute to tau aggregation.

Keywords

References

  1. Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubuleassociated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA. 1986;83:4913-4917. https://doi.org/10.1073/pnas.83.13.4913
  2. Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29:95-102. https://doi.org/10.1016/j.tibs.2003.12.004
  3. Lovestone S, Hartley CL, Pearce J, Anderton BH. Phosphorylation of tau by glycogen synthase kinase-3 beta in intact mammalian cells: the effects on the organization and stability of microtubules. Neuroscience. 1996;73:1145-1157. https://doi.org/10.1016/0306-4522(96)00126-1
  4. Leroy K, Boutajangout A, Authelet M, Woodgett JR, Anderton BH, Brion JP. The active form of glycogen synthase kinase-3beta is associated with granulovacuolar degeneration in neurons in Alzheimer's disease. Acta Neuropathol. 2002;103: 91-99. https://doi.org/10.1007/s004010100435
  5. Gamblin TC, Chen F, Zambrano A, Abraha A, Lagalwar S, Guillozet AL, Lu M, Fu Y, Garcia-Sierra F, LaPointe N, Miller R, Berry RW, Binder LI, Cryns VL. Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease. Proc Natl Acad Sci USA. 2003;100:10032-10037. https://doi.org/10.1073/pnas.1630428100
  6. Rissman RA, Poon WW, Blurton-Jones M, Oddo S, Torp R, Vitek MP, LaFerla FM, Rohn TT, Cotman CW. Caspasecleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest. 2004;114:121-130. https://doi.org/10.1172/JCI200420640
  7. Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends Mol Med. 2005;11:164-169. https://doi.org/10.1016/j.molmed.2005.02.008
  8. Lee YJ, Kim NY, Suh YA, Lee C. Involvement of ROS in curcumin-induced autophagic cell death. Korean J Physiol Pharmacol. 2010;15:1-7. https://doi.org/10.4196/kjpp.2011.15.1.1
  9. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443:780-786. https://doi.org/10.1038/nature05291
  10. Todde V, Veenhuis M, van der Klei IJ. Autophagy: principles and significance in health and disease. Biochim Biophys Acta. 2009;1792:3-13. https://doi.org/10.1016/j.bbadis.2008.10.016
  11. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;441:880-884. https://doi.org/10.1038/nature04723
  12. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA. Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. J Neurosci. 1996;16:186-199.
  13. Nakamura Y, Takeda M, Suzuki H, Hattori H, Tada K, Hariguchi S, Hashimoto S, Nishimura T. Abnormal distribution of cathepsins in the brain of patients with Alzheimer's disease. Neurosci Lett. 1991;130:195-198. https://doi.org/10.1016/0304-3940(91)90395-A
  14. Ding H, Matthews TA, Johnson GV. Site-specific phosphorylation and caspase cleavage differentially impact tau-microtubule interactions and tau aggregation. J Biol Chem. 2006; 281:19107-19114. https://doi.org/10.1074/jbc.M511697200
  15. Chun W, Johnson GV. Activation of glycogen synthase kinase 3beta promotes the intermolecular association of tau. The use of fluorescence resonance energy transfer microscopy. J Biol Chem. 2007;282:23410-23417. https://doi.org/10.1074/jbc.M703706200
  16. Cho JH, Johnson GV. Glycogen synthase kinase 3 beta induces caspase-cleaved tau aggregation in situ. J Biol Chem. 2004;279:54716-54723. https://doi.org/10.1074/jbc.M403364200
  17. Sun A, Nguyen XV, Bing G. Comparative analysis of an improved thioflavin-s stain, Gallyas silver stain, and immunohistochemistry for neurofibrillary tangle demonstration on the same sections. J Histochem Cytochem. 2002;50:463-472. https://doi.org/10.1177/002215540205000403
  18. Wang Y, Martinez-Vicente M, Krüger U, Kaushik S, Wong E, Mandelkow EM, Cuervo AM, Mandelkow E. Tau fragmentation, aggregation and clearance: the dual role of lysosomal processing. Hum Mol Genet. 2009;18:4153-4170. https://doi.org/10.1093/hmg/ddp367
  19. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alphasynuclein. J Biol Chem. 2007;282:5641-5652. https://doi.org/10.1074/jbc.M609532200
  20. Chun W, Waldo GS, Johnson GV. Split GFP complementation assay: a novel approach to quantitatively measure aggregation of tau in situ: effects of GSK3beta activation and caspase 3 cleavage. J Neurochem. 2007;103:2529-2539. https://doi.org/10.1111/j.1471-4159.2007.04941.x
  21. Sato S, Tatebayashi Y, Akagi T, Chui DH, Murayama M, Miyasaka T, Planel E, Tanemura K, Sun X, Hashikawa T, Yoshioka K, Ishiguro K, Takashima A. Aberrant tau phosphorylation by glycogen synthase kinase-3beta and JNK3 induces oligomeric tau fibrils in COS-7 cells. J Biol Chem. 2002;277: 42060-42065. https://doi.org/10.1074/jbc.M202241200
  22. Kuret J, Chirita CN, Congdon EE, Kannanayakal T, Li G, Necula M, Yin H, Zhong Q. Pathways of tau fibrillization. Biochim Biophys Acta. 2005;1739:167-178. https://doi.org/10.1016/j.bbadis.2004.06.016
  23. Feuillette S, Blard O, Lecourtois M, Frebourg T, Campion D, Dumanchin C. Tau is not normally degraded by the proteasome. J Neurosci Res. 2005;80:400-405. https://doi.org/10.1002/jnr.20414
  24. McCray BA, Taylor JP. The role of autophagy in age-related neurodegeneration. Neurosignals. 2008;16:75-84. https://doi.org/10.1159/000109761
  25. Hamano T, Gendron TF, Causevic E, Yen SH, Lin WL, Isidoro C, Deture M, Ko LW. Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wildtype tau expression. Eur J Neurosci. 2008;27:1119-1130. https://doi.org/10.1111/j.1460-9568.2008.06084.x
  26. Rankin CA, Sun Q, Gamblin TC. Pseudo-phosphorylation of tau at Ser202 and Thr205 affects tau filament formation. Brain Res Mol Brain Res. 2005;138:84-93. https://doi.org/10.1016/j.molbrainres.2005.04.012
  27. Schneider A, Biernat J, von Bergen M, Mandelkow E, Mandelkow EM. Phosphorylation that detaches tau protein from microtubules (Ser262, Ser214) also protects it against aggregation into Alzheimer paired helical filaments. Biochemistry. 1999;38: 3549-3558. https://doi.org/10.1021/bi981874p
  28. Poppek D, Keck S, Ermak G, Jung T, Stolzing A, Ullrich O, Davies KJ, Grune T. Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress. Biochem J. 2006;400:511-520. https://doi.org/10.1042/BJ20060463
  29. Alonso A, Zaidi T, Novak M, Grundke-Iqbal I, Iqbal K. Hyperphosphorylation induces self-assembly of tau into tangles of paired helical filaments/straight filaments. Proc Natl Acad Sci USA. 2001;98:6923-6928. https://doi.org/10.1073/pnas.121119298
  30. Chun W, Johnson GV. The role of tau phosphorylation and cleavage in neuronal cell death. Front Biosci. 2007;12:733-756. https://doi.org/10.2741/2097

Cited by

  1. The Ambiguous Relationship of Oxidative Stress, Tau Hyperphosphorylation, and Autophagy Dysfunction in Alzheimer's Disease vol.2015, pp.None, 2015, https://doi.org/10.1155/2015/352723
  2. The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease vol.28, pp.8, 2011, https://doi.org/10.1515/revneuro-2017-0013
  3. The role of ubiquitin proteasomal system and autophagy-lysosome pathway in Alzheimer’s disease vol.28, pp.8, 2011, https://doi.org/10.1515/revneuro-2017-0013
  4. Autophagic dysfunction in Alzheimer’s disease: Cellular and molecular mechanistic approaches to halt Alzheimer’s pathogenesis vol.234, pp.6, 2011, https://doi.org/10.1002/jcp.27588
  5. Exploring the multifunctional role of melatonin in regulating autophagy and sleep to mitigate Alzheimer’s disease neuropathology vol.67, pp.None, 2011, https://doi.org/10.1016/j.arr.2021.101304