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Volume 21, Issue 4
  • ISSN: 1567-2050
  • E-ISSN: 1875-5828

Abstract

Background

Neurodegenerative disorders like Alzheimer's disease (AD) involve the abnormal aggregation of tau protein, which forms toxic oligomers and amyloid deposits. The structure of tau protein is influenced by the conformational states of distinct proline residues, which are regulated by peptidyl-prolyl isomerases (PPIases). However, there has been no research on the impact of human cyclophilin A (CypA) as a PPIase on (non-phosphorylated) tau protein aggregation.

Methods

On the basis of these explanations, we used various spectroscopic techniques to explore the effects of CypA on tau protein aggregation behavior.

Results

We demonstrated the role of the isomerization activity of CypA in promoting the formation of tau protein amyloid fibrils with well-defined and highly ordered cross-β structures. According to the “cistauosis hypothesis,” CypA's ability to enhance tau protein fibril formation in AD is attributed to the isomerization of specific proline residues from the to configuration. To corroborate this theory, we conducted refolding experiments using lysozyme as a model protein. The presence of CypA increased lysozyme aggregation and impeded its refolding process. It is known that proper refolding of lysozyme relies on the correct () isomerization of two critical proline residues.

Conclusion

Thus, our findings confirmed that CypA induces the -to- isomerization of specific proline residues, ultimately leading to increased aggregation. Overall, this study highlights the emerging role of isomerization in tau protein pathogenesis in AD.

© 2024 Bentham Science Publishers
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2024-04-01
2024-11-23

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References

  1. McKhannG.M. KnopmanD.S. ChertkowH. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging‐Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease.Alzheimers Dement.20117326326910.1016/j.jalz.2011.03.005 21514250
     [Google Scholar]
  2. FazelinejadH. ZahediE. NazarianS. Neuroprotective effect of Bis(Indolyl)phenylmethane in Alzheimer’s disease rat model through inhibition of hen Lysozyme amyloid fibril-induced neurotoxicity.J. Indian Chem. Soc.202320355156210.1007/s13738‑022‑02692‑8
     [Google Scholar]
  3. AkbariV. BahramikiaS. JalalvandA.R. MehrabiM. EzatiM. KhodarahmiR. The induction of tau aggregation is restricted by sulfamethoxazole and provides new information regarding the use of the drug.J. Biomol. Struct. Dyn.20231911510.1080/07391102.2023.2273433 37878050
     [Google Scholar]
  4. BallatoreC. LeeV.M.Y. TrojanowskiJ.Q. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders.Nat. Rev. Neurosci.20078966367210.1038/nrn2194 17684513
     [Google Scholar]
  5. AkbariV. MohammadiS. MehrabiM. GhobadiS. FarrokhiA. KhodarahmiR. Investigation of the role of prolines 232/233 in RTPPK motif in tau protein aggregation: An in vitro study.Int. J. Biol. Macromol.20222191100111110.1016/j.ijbiomac.2022.08.160 36049563
     [Google Scholar]
  6. LuK.P. LiouY.C. VincentI. Proline‐directed phosphorylation and isomerization in mitotic regulation and in Alzheimer’s Disease.BioEssays200325217418110.1002/bies.10223 12539244
     [Google Scholar]
  7. HamanoT. EnomotoS. ShirafujiN. Autophagy and tau protein.Int. J. Mol. Sci.20212214747510.3390/ijms22147475 34299093
     [Google Scholar]
  8. DolanP.J. JohnsonG.V. The role of tau kinases in Alzheimer’s disease.Curr. Opin. Drug Discov. Devel.2010135595603 20812151
     [Google Scholar]
  9. NakamuraK. GreenwoodA. BinderL. Proline isomer-specific antibodies reveal the early pathogenic tau conformation in Alzheimer’s disease.Cell2012149123224410.1016/j.cell.2012.02.016 22464332
     [Google Scholar]
  10. LuK.P. KondoA. AlbayramO. HerbertM.K. LiuH. ZhouX.Z. Potential of the antibody against cis–phosphorylated tau in the early diagnosis, treatment, and prevention of Alzheimer disease and brain injury.JAMA Neurol.201673111356136210.1001/jamaneurol.2016.2027 27654282
     [Google Scholar]
  11. YaffeM.B. SchutkowskiM. ShenM. Sequence-specific and phosphorylation-dependent proline isomerization: a potential mitotic regulatory mechanism.Science199727853451957196010.1126/science.278.5345.1957 9395400
     [Google Scholar]
  12. LuK.P. Pinning down cell signaling, cancer and Alzheimer’s disease.Trends Biochem. Sci.200429420020910.1016/j.tibs.2004.02.002 15082314
     [Google Scholar]
  13. LuK.P. FinnG. LeeT.H. NicholsonL.K. Prolyl cis-trans isomerization as a molecular timer.Nat. Chem. Biol.200731061962910.1038/nchembio.2007.35 17876319
     [Google Scholar]
  14. ZeronianM.R. DoulkeridouS. van Bergen en HenegouwenPMP JanssenBJC. Structural insights into the non-inhibitory mechanism of the anti-EGFR EgB4 nanobody.BMC Mol. Cell Biol.20222311210.1186/s12860‑022‑00412‑x 35232398
     [Google Scholar]
  15. BlairL.J. BakerJ.D. SabbaghJ.J. DickeyC.A. The emerging role of peptidyl‐prolyl isomerase chaperones in tau oligomerization, amyloid processing, and Alzheimer’s disease.J. Neurochem.2015133111310.1111/jnc.13033 25628064
     [Google Scholar]
  16. ŠimićG. Babić LekoM. WrayS. Tau protein hyperphosphorylation and aggregation in Alzheimer’s disease and other tauopathies, and possible neuroprotective strategies.Biomolecules201661610.3390/biom6010006 26751493
     [Google Scholar]
  17. ChenZ.J. VetterM. ChangG.D. Cyclophilin A functions as an endogenous inhibitor for membrane-bound guanylate cyclase-A.Hypertension200444696396810.1161/01.HYP.0000145859.94894.23 15466660
     [Google Scholar]
  18. SongJ. LuY.C. YokoyamaK. RossiJ. ChiuR. Cyclophilin A is required for retinoic acid-induced neuronal differentiation in p19 cells.J. Biol. Chem.200427923244142441910.1074/jbc.M311406200 15047706
     [Google Scholar]
  19. GöldnerF.M. PatrickJ.W. Neuronal localization of the cyclophilin A protein in the adult rat brain.J. Comp. Neurol.1996372228329310.1002/(SICI)1096‑9861(19960819)372:2<283::AID‑CNE9>3.0.CO;2‑# 8863131
     [Google Scholar]
  20. OjaghiS. MohammadiS. AmaniM. Sunset yellow degradation product, as an efficient water-soluble inducer, accelerates 1N4R Tau amyloid oligomerization: In vitro preliminary evidence against the food colorant safety in terms of “Triggered Amyloid Aggregation”.Bioorg. Chem.202010310412310.1016/j.bioorg.2020.104123 32781343
     [Google Scholar]
  21. MehrabiM. BijariN. AkbariV. Effective reduction of tau amyloid aggregates in the presence of cyclophilin from Platanus orientalis pollens; An alternative mechanism of action of the allergen.Curr. Protein Pept. Sci.202324651853210.2174/1389203724666230530143704 37259218
     [Google Scholar]
  22. LowryO. RosebroughN. FarrA.L. RandallR. Protein measurement with the Folin phenol reagent.J. Biol. Chem.1951193126527510.1016/S0021‑9258(19)52451‑6 14907713
     [Google Scholar]
  23. KhademiF. HamzeheeK. MostafaieA. HajihossainiR. Purification of three major forms of β-hCG from urine and production of polyclonal antibodies against them.Clin. Biochem.20094213-141476148210.1016/j.clinbiochem.2009.05.019 19501580
     [Google Scholar]
  24. FarinaB. Di SorboG. ChamberyA. Structural and biochemical insights of CypA and AIF interaction.Sci. Rep.201771113810.1038/s41598‑017‑01337‑8 28442737
     [Google Scholar]
  25. Sambrook, J.; Russell, D.W. Molecular Cloning: Ch. 8. In Vitro amplification of DNA by the polymerase chain reaction. Vol. 2.Cold Spring Harbor Laboratory Press2001
     [Google Scholar]
  26. SongF. ZhangX. RenX.B. Cyclophilin A (CyPA) induces chemotaxis independent of its peptidylprolyl cis-trans isomerase activity: direct binding between CyPA and the ectodomain of CD147.J. Biol. Chem.2011286108197820310.1074/jbc.C110.181347 21245143
     [Google Scholar]
  27. MoparthiS.B. HammarströmP. CarlssonU. A nonessential role for Arg 55 in cyclophilin18 for catalysis of proline isomerization during protein folding.Protein Sci.200918247547910.1002/pro.28 19185003
     [Google Scholar]
  28. FischerG. BangH. BergerE. SchellenbergerA. Conformational specificity of chymotrypsin toward proline-containing substrates.Biochim. Biophys. Acta Protein Struct. Mol. Enzymol.19847911879710.1016/0167‑4838(84)90285‑1 6498206
     [Google Scholar]
  29. HudsonS.A. EcroydH. KeeT.W. CarverJ.A. The thioflavin T fluorescence assay for amyloid fibril detection can be biased by the presence of exogenous compounds.FEBS J.2009276205960597210.1111/j.1742‑4658.2009.07307.x 19754881
     [Google Scholar]
  30. XueC. LinT.Y. ChangD. GuoZ. Thioflavin T as an amyloid dye: fibril quantification, optimal concentration and effect on aggregation.R. Soc. Open Sci.201741160696 28280572
     [Google Scholar]
  31. JangholiA. Ashrafi-KooshkM.R. ArabS.S. Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study.Arch. Biochem. Biophys.201660911910.1016/j.abb.2016.09.004 27638048
     [Google Scholar]
  32. KhodarahmiR. BeyramiM. SooriH. Appraisal of casein’s inhibitory effects on aggregation accompanying carbonic anhydrase refolding and heat-induced ovalbumin fibrillogenesis.Arch. Biochem. Biophys.20084771677610.1016/j.abb.2008.04.028 18485276
     [Google Scholar]
  33. HurS. BruiceT.C. The mechanism of cis-trans isomerization of prolyl peptides by cyclophilin.J. Am. Chem. Soc.2002124257303731310.1021/ja020222s 12071739
     [Google Scholar]
  34. LiG. CuiQ. What is so special about Arg 55 in the catalysis of cyclophilin A? insights from hybrid QM/MM simulations.J. Am. Chem. Soc.200312549150281503810.1021/ja0367851 14653737
     [Google Scholar]
  35. InouyeH. SharmaD. GouxW.J. KirschnerD.A. Structure of core domain of fibril-forming PHF/Tau fragments.Biophys. J.20069051774178910.1529/biophysj.105.070136 16339876
     [Google Scholar]
  36. LührsT. RitterC. AdrianM. 3D structure of Alzheimer’s amyloid-β(1–42) fibrils.Proc. Natl. Acad. Sci. USA200510248173421734710.1073/pnas.0506723102 16293696
     [Google Scholar]
  37. BrownN.R. NobleM.E.M. EndicottJ.A. JohnsonL.N. The structural basis for specificity of substrate and recruitment peptides for cyclin-dependent kinases.Nat. Cell Biol.19991743844310.1038/15674 10559988
     [Google Scholar]
  38. ZhouX.Z. KopsO. WernerA. Pin1-dependent prolyl isomerization regulates dephosphorylation of Cdc25C and tau proteins.Mol. Cell20006487388310.1016/S1097‑2765(05)00083‑3 11090625
     [Google Scholar]
  39. LimJ. BalastikM. LeeT.H. Pin1 has opposite effects on wild-type and P301L tau stability and tauopathy.J. Clin. Invest.200811851877188910.1172/JCI34308 18431510
     [Google Scholar]
  40. PoppekD. KeckS. ErmakG. Phosphorylation inhibits turnover of the tau protein by the proteasome: influence of RCAN1 and oxidative stress.Biochem. J.2006400351152010.1042/BJ20060463 16939415
     [Google Scholar]
  41. LuP.J. WulfG. ZhouX.Z. DaviesP. LuK.P. The prolyl isomerase Pin1 restores the function of Alzheimer-associated phosphorylated tau protein.Nature1999399673878478810.1038/21650 10391244
     [Google Scholar]
  42. Luna-MuñozJ. Chávez-MacíasL. García-SierraF. MenaR. Earliest stages of tau conformational changes are related to the appearance of a sequence of specific phospho-dependent tau epitopes in Alzheimer’s disease.J. Alzheimers Dis.200712436537510.3233/JAD‑2007‑12410 18198423
     [Google Scholar]
  43. KondoA. ShahpasandK. MannixR. Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy.Nature2015523756143143610.1038/nature14658 26176913
     [Google Scholar]
  44. ColganJ. AsmalM. NeaguM. Cyclophilin A regulates TCR signal strength in CD4+ T cells via a proline-directed conformational switch in Itk.Immunity200421218920110.1016/j.immuni.2004.07.005 15308100
     [Google Scholar]
  45. BrazinK.N. MallisR.J. FultonD.B. AndreottiA.H. Regulation of the tyrosine kinase Itk by the peptidyl-prolyl isomerase cyclophilin A.Proc. Natl. Acad. Sci. USA20029941899190410.1073/pnas.042529199 11830645
     [Google Scholar]
  46. HarrisonR.K. SteinR.L. Substrate specificities of the peptidyl prolyl cis-trans isomerase activities of cyclophilin and FK-506 binding protein: evidence for the existence of a family of distinct enzymes.Biochemistry199029163813381610.1021/bi00468a001 1693856
     [Google Scholar]
  47. BakerJ.D. SheltonL.B. ZhengD. Human cyclophilin 40 unravels neurotoxic amyloids.PLoS Biol.2017156e200133610.1371/journal.pbio.2001336 28654636
     [Google Scholar]
  48. ZhaoY. KeH. Crystal structure implies that cyclophilin predominantly catalyzes the trans to cis isomerization.Biochemistry199635237356736110.1021/bi9602775 8652511
     [Google Scholar]
  49. BarronS.E. Misfolded forms of hen egg white lysozyme.United KingdomUniversity of Glasgow2001
     [Google Scholar]
  50. RajanR. AhmedS. SharmaN. KumarN. DebasA. MatsumuraK. Review of the current state of protein aggregation inhibition from a materials chemistry perspective: special focus on polymeric materials.Materials Advances2021241139117610.1039/D0MA00760A
     [Google Scholar]
  51. LimorenkoG. LashuelH.A. Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies.Chem. Soc. Rev.202251251356510.1039/D1CS00127B 34889934
     [Google Scholar]
  52. FavrettoF. FloresD. BakerJ.D. Catalysis of proline isomerization and molecular chaperone activity in a tug-of-war.Nat. Commun.2020111604610.1038/s41467‑020‑19844‑0 33247146
     [Google Scholar]
  53. HillS.E. EsquivelA.R. OspinaS.R. RahalL.M. DickeyC.A. BlairL.J. Chaperoning activity of the cyclophilin family prevents tau aggregation.Protein Sci.20223111e444810.1002/pro.4448 36305768
     [Google Scholar]
  54. MaedaS. SatoY. TakashimaA. Frontotemporal dementia with Parkinsonism linked to chromosome-17 mutations enhance tau oligomer formation.Neurobiol. Aging201869263210.1016/j.neurobiolaging.2018.04.014 29852407
     [Google Scholar]
/content/journals/car/10.2174/0115672050330163240812050223
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“Cyclophilin A” Enzymatic Effect on the Aggregation Behavior of 1N4R Tau Protein: An Overlooked Crucial Determinant that should be Re-considered in Alzheimer's Disease Pathogenesis
Curr Alzheimer Res 21, 242 (2024); https://doi.org/10.2174/0115672050330163240812050223
/content/journals/car/10.2174/0115672050330163240812050223
/content/journals/car/10.2174/0115672050330163240812050223
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  • Article Type:     Research Article
Keyword(s): Alzheimer's disease (AD); amyloid aggregation; cyclophilin A (CypA); disaggregation; refolding; tau protein

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